Sulfonamides for treatment of endothelin-mediated disorders

ABSTRACT

Thienylsulfonamides and their pharmaceutically acceptable derivatives, pharmaceutical compositions, articles of manufacture, combinations, lyophilized powders and methods for the treatment of endothelin diseases using these formulations and sulfonamides are provided. A process of preparing an alkali metal salt of a hydrophobic sulfonamide is provided. The process includes the step of dissolving a free sulfonamide in an organic solvent in the presence of a saturated alkali metal salt solution and recovering the formed sulfonamide salt from the organic phase.

RELATED APPLICATIONS

This application is a divisional application of allowed U.S. applicationSer. No. 09/403,599, to Wu et al., filed Mar. 27, 2000 now U.S. Pat. No.6,432,944 B1, entitled “SULFONAMIDES FOR TREATMENT OFENDOTHELIN-MEDIATED DISORDERS”.

For U.S. national stage purposes, this application is acontinuation-in-part of U.S. application Ser. No. 08/938,444, now U.S.Pat. No. 6,248,767, to Blok et al., filed Sep. 26, 1997, entitled“FORMULATION OF SULFONAMIDES FOR TREATMENT OF ENDOTHELIN-MEDIATEDDISORDERS”. This application is also a continuation-in-part of U.S.application Ser. No. 08/847,797, now U.S. Pat. No. 5,783,705, to Blok etal., filed Apr. 28, 1997, entitled “PROCESS OF PREPARING ALKALI METALSALTS OF HYDROPHOBIC SULFONAMIDES”. For international purposes, thebenefit of priority is hereby claimed to the above-referencedapplications.

This application is related to allowed U.S. application Ser. No.08/938,325 to Wu et al., filed Sep. 26, 1997, entitled “SULFONAMIDES ANDDERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN,” and isalso related to International application No. PCT/US97/17402, now PCTInternational Publication No. WO 98/13366, to Wu et al., filed Sep. 26,1997, entitled “SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THEACTIVITY OF ENDOTHELIN”. This application is related to U.S. applicationSer. No. 08/721,183, now U.S. Pat. No. 5,962,490, to Chan et al., filedSep. 27, 1996, entitled “SULFONAMIDES AND DERIVATIVES THEREOF THATMODULATE THE ACTIVITY OF ENDOTHELIN”; is also a related to InternationalPCT application No. PCT/US96/04759 to Chan et al., filed Apr. 4, 1996,entitled “THIENYL, FURYL-, PYRROLYL- AND BIPHENYLSULFONAMIDES ANDDERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN”; is alsorelated to U.S. application Ser. No. 08/477,223, now U.S. Pat. No.5,594,021, to Chan et al., filed Jun. 6, 1995, entitled “THIENYL-,FURYL- AND PYRROLYL SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATETHE ACTIVITY OF ENDOTHELIN”; is also related to U.S. application Ser.No. 08/417,075 to Chan et al., filed Apr. 4, 1995, entitled “THIENYL-,FURYL- AND PYRROLYL SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATETHE ACTIVITY OF ENDOTHELIN”, now abandoned; is also related to U.S.application Ser. No. 08/247,072, now U.S. Pat. No. 5,571,821, to Chan etal., filed May 20, 1994, entitled “SULFONAMIDES AND DERIVATIVES THEREOFTHAT MODULATE THE ACTIVITY OF ENDOTHELIN”; is also related to U.S.application Ser. No. 08/222,287, now U.S. Pat. No. 5,591,761, to Chan etal., filed Apr. 5, 1994, entitled “THIOPHENYL-, FURYL- ANDPYRROLYL-SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITYOF ENDOTHELIN”; each of these applications is related to U.S.application Ser. No. 08/142,552, now U.S. Pat. No. 5,514,691, to Chan etal., filed Oct. 21, 1993, entitled “N-(4-HALO-ISOXAZOLYL)-SULFONAMIDESAND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN”; U.S.application Ser. No. 08/142,159, now U.S. Pat. No. 5,464,853, to Chan etal., filed Oct. 21, 1993, entitled“N-(5-ISOXAZOLYL)BIPHENYLSULFONAMIDES,N-(3-ISOXAZOLYL)BIPHENYLSULFONAMIDES AND DERIVATIVES THEREOF THATMODULATE THE ACTIVITY OF ENDOTHELIN”; and U.S. application Ser. No.08/142,631 to Chan et al., filed Oct. 21, 1993, entitled“N-(5-ISOXAZOLYL)-BENZENESULFONAMIDES,N-(3-ISOXAZOLYL)-BENZENESULFONAMIDES AND DERIVATIVES THEREOF THATMODULATE THE ACTIVITY OF ENDOTHELIN”, now abandoned.

Where permitted, the subject matter of each of the above-notedapplications is herein incorporated in its entirety by referencethereto.

FIELD OF THE INVENTION

The present invention relates to compounds and formulations thereof foradministration to mammals that modulate the activity of the endothelinfamily of peptides. In particular, sulfonamides and formulations ofsulfonamide compounds, especially sodium salts of sulfonamide compounds,for administration for treatment of endothelin-mediated disorders areprovided. Also provided is a process for preparing alkali metal salts ofhydrophobic sulfonamides.

BACKGROUND OF THE INVENTION

The vascular endothelium releases a variety of vasoactive substances,including the endothelium-derived vasoconstrictor peptide, endothelin(ET) (see, e.g., Vanhoutte et al. (1986) Annual Rev. Physiol.48:307-320; Furchgott and Zawadski (1980) Nature 288:373-376).Endothelin, which was originally identified in the culture supernatantof porcine aortic endothelial cells (see, Yanagisawa et al. (1988)Nature 332:411-415), is a potent twenty-one amino acid peptidevasoconstrictor. It is the most potent vasopressor known and is producedby numerous cell types, including the cells of the endothelium, trachea,kidney and brain. Endothelin is synthesized as a two hundred and threeamino acid precursor preproendothelin that contains a signal sequencewhich is cleaved by an endogenous protease to produce a thirty-eight(human) or thirty-nine (porcine) amino acid peptide. This intermediate,referred to as big endothelin, is processed in vivo to the maturebiologically active form by a putative endothelin-converting enzyme(ECE) that appears to be a metal-dependent neutral protease (see, e.g,Kashiwabara et al. (1989) FEBS Lttrs. 247:337-340). Cleavage is requiredfor induction of physiological responses (see, e.g, von Geldern et al.(1991) Peptide Res. 4:32-35). In porcine aortic endothelial cells, thethirty-nine amino acid intermediate, big endothelin, is hydrolyzed atthe Trp²¹-Val²² bond to generate endothelin-1 and a C-terminal fragment.A similar cleavage occurs in human cells from a thirty-eight amino acidintermediate. Three distinct endothelin isopeptides, endothelin-1,endothelin-2 and endothelin-3, that exhibit potent vasoconstrictoractivity have been identified.

The family of three isopeptides endothelin-1, endothelin-2 andendothelin-3 are encoded by a family of three genes (see, Inoue et al.(1989) Proc. Natl. Acad. Sci. USA 86:2863-2867; see, also Saida et al.(1989) J. Biol. Chem. 264:14613-14616). The nucleotide sequences of thethree human genes are highly conserved within the region encoding themature 21 amino acid peptides and the C-terminal portions of thepeptides are identical. Endothelin-2 is (Trp⁶,Leu⁷) endothelin-1 andendothelin-3 is (Thr²,Phe⁴,Thr⁵,Tyr⁶,Lys⁷,Tyr¹⁴) endothelin-1. Thesepeptides are, thus, highly conserved at the C-terminal ends. Release ofendothelins from cultured endothelial cells is modulated by a variety ofchemical and physical stimuli and appears to be regulated at the levelof transcription and/or translation. Expression of the gene encodingendothelin-1 is increased by chemical stimuli, including adrenaline,thrombin and Ca²⁺ ionophore. The production and release of endothelinfrom the endothelium is stimulated by angiotensin II, vasopressin,endotoxin, cyclosporine and other factors (see, Brooks et al. (1991)Eur. J. Pharm. 194:115-117), and is inhibited by nitric oxide.Endothelial cells appear to secrete short-lived endothelium-derivedrelaxing factors (EDRF), including nitric oxide or a related substance(Palmer et al. (1987) Nature 327:524-526), when stimulated by vasoactiveagents, such as acetylcholine and bradykinin. Endothelin-inducedvasoconstriction is also attenuated by atrial natriuretic peptide (ANP).

The endothelin peptides exhibit numerous biological activities in vitroand in vivo. Endothelin provokes a strong and sustained vasoconstrictionin vivo in rats and in isolated vascular smooth muscle preparations; italso provokes the release of eicosanoids and endothelium-derivedrelaxing factor (EDRF) from perfused vascular beds. Intravenousadministration of endothelin-1 and in vitro addition to vascular andother smooth muscle tissues produce long-lasting pressor effects andcontraction, respectively (see, eq., Bolger et al. (1991) Can. J.Physiol. Pharmacol. 69:406-413). In isolated vascular strips, forexample, endothelin-1 is a potent (EC₅₀=4×10⁻¹⁰ M), slow acting, butpersistent, contractile agent. In vivo, a single dose elevates bloodpressure in about twenty to thirty minutes. Endothelin-inducedvasoconstriction is not affected by antagonists to knownneurotransmitters or hormonal factors, but is abolished by calciumchannel antagonists. The effect of calcium channel antagonists, however,is most likely the result of inhibition of calcium influx, since calciuminflux appears to be required for the long-lasting contractile responseto endothelin.

Endothelin also mediates renin release, stimulates ANP release andinduces a positive inotropic action in guinea pig atria. In the lung,endothelin-1 acts as a potent bronchoconstrictor (Maggi et al. (1989)Eur. J. Pharmacol. 160:179-182). Endothelin increases renal vascularresistance, decreases renal blood flow, and decreases glomerularfiltrate rate. It is a potent mitogen for glomerular mesangial cells andinvokes the phosphoinoside cascade in such cells (Simonson et al. (1990)J. Clin. Invest. 85:790-797).

There are specific high affinity binding sites (dissociation constantsin the range of 2-6×10⁻¹⁰ M) for the endothelins in the vascular systemand in other tissues, including the intestine, heart, lungs, kidneys,spleen, adrenal glands and brain. Binding is not inhibited bycatecholamines, vasoactive peptides, neurotoxins or calcium channelantagonists. Endothelin binds and interacts with receptor sites that aredistinct from other autonomic receptors and voltage dependent calciumchannels. Competitive binding studies indicate that there are multipleclasses of receptors with different affinities for the endothelinisopeptides. The sarafotoxins, a group of peptide toxins from the venomof the snake Atractaspis eingadensis that cause severe coronaryvasospasm in snake bite victims, have structural and functional homologyto endothelin-1 and bind competitively to the same cardiac membranereceptors (Kloog et al. (1989) Trends Pharmacol. Sci. 10:212-214).

Two distinct endothelin receptors, designated ET_(A) and ET_(B), havebeen identified and DNA clones encoding each receptor have been isolated(Arai et al. (1990) Nature 348:730-732; Sakurai et al. (1990) Nature348:732-735). Based on the amino acid sequences of the proteins encodedby the cloned DNA, it appears that each receptor contains seven membranespanning domains and exhibits structural similarity to G-protein-coupledmembrane proteins. Messenger RNA encoding both receptors has beendetected in a variety of tissues, including heart, lung, kidney andbrain. The distribution of receptor subtypes is tissue specific (Martinet al. (1989) Biochem. Biophys. Res. Commun. 162:130-137). ET_(A)receptors appear to be selective for endothelin-1 and are predominant incardiovascular tissues. E_(TB) receptors are predominant innoncardiovascular tissues, including the central nervous system andkidney, and interact with the three endothelin isopeptides (Sakurai etal. (1990) Nature 348:732-734). In addition, ET_(A) receptors occur onvascular smooth muscle, are linked to vasoconstriction and have beenassociated with cardiovascular, renal and central nervous systemdiseases; whereas ET_(B) receptors are located on the vascularendothelium, linked to vasodilation (Takayanagi et al. (1991) FEBSLttrs. 282:103-106) and have been associated with bronchoconstrictivedisorders.

By virtue of the distribution of receptor types and the differentialaffinity of each isopeptide for each receptor type, the activity of theendothelin isopeptides varies in different tissues. For example,endothelin-1 inhibits ¹²⁵I-labelled endothelin-1 binding incardiovascular tissues forty to seven hundred times more potently thanendothelin-3. ¹²⁵l-labelled endothelin-1 binding in non-cardiovasculartissues, such as kidney, adrenal gland, and cerebellum, is inhibited tothe same extent by endothelin-1 and endothelin-3, which indicates thatETA receptors predominate in cardiovascular tissues and ET_(B) receptorspredominate in non-cardiovascular tissues.

Endothelin plasma levels are elevated in certain disease states (see,e.g., International PCT Application WO 94/27979, and U.S. Pat. No.5,382,569, which disclosures are herein incorporated in their entiretyby reference). Endothelin-1 plasma levels in healthy individuals, asmeasured by radioimmunoassay (RIA), are about 0.26-5 pg/ml. Blood levelsof endothelin-1 and its precursor, big endothelin, are elevated inshock, myocardial infarction, vasospastic angina, kidney failure and avariety of connective tissue disorders. In patients undergoinghemodialysis or kidney transplantation or suffering from cardiogenicshock, myocardial infarction or pulmonary hypertension levels as high as35 pg/ml have been observed (see, Stewart et al. (1991) Annals InternalMed. 114:464-469). Because endothelin is likely to be a local, ratherthan a systemic, regulating factor, it is probable that the levels ofendothelin at the endothelium/smooth muscle interface are much higherthan circulating levels.

Elevated levels of endothelin have also been measured in patientssuffering from ischemic heart disease (Yasuda et al. (1990) Amer. HeartJ. 119:801-806, Ray et al. (1992) Br. Heart J. 67:383-386). Circulatingand tissue endothelin immunoreactivity is increased more than twofold inpatients with advanced atherosclerosis (Lerman et al. (1991) New Engl.J. Med. 325:997-1001). Increased endothelin immunoreactivity has alsobeen associated with Buerger's disease (Kanno et al. (1990) J. Amer.Med. Assoc. 264:2868) and Raynaud's phenomenon (Zamora et al. (1990)Lancet 336 1144-1147). Increased circulating endothelin levels wereobserved in patients who underwent percutaneous transluminal coronaryangioplasty (PTCA) (Tahara et al. (1991) Metab. Clin. Exp. 40:1235-1237;Sanjay et al. (1991) Circulation 84(Suppl. 4):726), and in individuals(Miyauchi et al. (1992) Jpn. J. Pharmacol. 58:279P; Stewart et al.(1991) Ann. Internal Medicine 114:464-469) with pulmonary hypertension.Thus, there is clinical human data supporting the correlation betweenincreased endothelin levels and numerous disease states.

Endothelin Agonists and Antagonists

Because endothelin is associated with certain disease states and isimplicated in numerous physiological effects, compounds that caninterfere with or potentiate endothelin-associated activities, such asendothelin-receptor interaction and vasoconstrictor activity, are ofinterest. Compounds that exhibit endothelin antagonistic activity havebeen identified. For example, a fermentation product of Streptomycesmisakiensis, designated BE-18257B, has been identified as an ET_(A)receptor antagonist. BE-18257B is a cyclic pentapeptide,cyclo(D-Glu-L-Ala-allo-D-lle-L-Leu-D-Trp) which inhibits ¹²⁵I-labelledendothelin-1 binding in cardiovascular tissues in aconcentration-dependent manner (IC₅₀ 1.4 μM in aortic smooth muscle, 0.8μM in ventricle membranes and 0.5 μM in cultured aortic smooth musclecells), but fails to inhibit binding to receptors in tissues in whichET_(B) receptors predominate at concentrations up to 100 μM. Cyclicpentapeptides related to BE-18257B, such ascyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123), have been synthesized andshown to exhibit activity as ET_(A) receptor antagonists (see, U.S. Pat.No. 5,114,918 to Ishikawa et al.; see, also, EP A1 0 436 189 to BANYUPHARMACEUTICAL CO., LTD (Oct. 7, 1991)). Studies that measure theinhibition by these cyclic peptides of endothelin-1 binding toendothelin-specific receptors indicate that these cyclic peptides bindpreferentially to ET_(A) receptors. Other peptide and non-peptidicET_(A) antagonists have been identified (see, e.g., U.S. Pat. Nos.5,352,800, 5,334,598, 5,352,659, 5,248,807, 5,240,910, 5,198,548,5,187,195, 5,082,838). These include other cyclic pentapeptides,acyltripeptides, hexapeptide analogs, certain anthraquinone derivatives,indanecarboxylic acids, certain N-pyriminylbenzenesulfonamides certainbenzenesulfonamides, and certain naphthalenesulfonamides (Nakajima etal. (1991) J. Antibiot. 44:1348-1356; Miyata et al. (1992) J. Antibiot.45:74-8; Ishikawa et al. (1992) J. Med. Chem. 35:2139-2142; U.S. Pat.No. 5,114,918 to Ishikawa et al.; EP A1 0 569 193; EP A1 0 558 258; EPA1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD (Oct. 7, 1991); CanadianPatent Application 2,067,288; Canadian Patent Application 2,071,193;U.S. Pat. No. 5,208,243; U.S. Pat. No. 5,270,313; U.S. Pat. No.5,612,359, U.S. Pat. No. 5,514,696, U.S. Pat. No. 5,378,715 Cody et al.(1993) Med. Chem. Res. 3:154-162; Miyata et al. (1992) J. Antibiot45:1041-1046; Miyata et al. (1992) J. Antibiot 45:1029-1040, Fujimoto etal. (1992) FEBS Lett. 305:41-44; Oshashi et el. (1002) J. Antibiot45:1684-1685; EP A1 0 496 452; Clozel et al. (1993) Nature 365:759-761;International Patent Application W093/08799; Nishikibe et al. (1993)Life Sci. 52:717-724; and Benigni et al. (1993) Kidney Int. 44:440-444).Numerous sulfonamides that are endothelin peptide antagonists are alsodescribed in U.S. Pat. Nos. 5,464,853, 5,594,021, 5,591,761, 5,571,821,5,514,691, 5,464,853, International PCT application No. 96/31492 andInternational PCT application No. WO 94/27979.

In general, the identified compounds have activities in in vitro assaysas ET_(A) antagonists at concentrations on the order of about 50-100 μMand less. A number of such compounds have also been shown to possessactivity in in vivo animal models.

Endothelin Antagonists and Agonists as Therapeutic Agents

In view of the numerous physiological effects of endothelin and itsassociation with certain diseases, endothelin is believed to play acritical role in these pathophysiological conditions (see, e.g., Saitoet al (1990) Hypertension 15:734-738; Tomita et al. (1989) N. Engl. J.Med. 321:1127; Kurihara et al. (1989) J. Cardiovasc. Pharmacol.13(Suppl. 5): S13-S17; Doherty (1992) J. Med. Chem. 35:1493-1508; Morelet al. (1989) Eur. J. Pharmacol. 167:427-428). More detailed knowledgeof the function and structure of the endothelin peptide family shouldprovide insight in the progression and treatment of such conditions.

Stable formulations of these compounds in a pharmaceutically acceptablevehicle are needed in order to use the compounds in these ways.

It has been recognized that compounds that exhibit activity at IC₅₀ orEC₅₀ concentrations on the order of 10⁻⁴ or lower in standard in vitroassays that assess endothelin antagonist or agonist activity havepharmacological utility (see, eqg, U.S. Pat. Nos. 5,352,800, 5,334,598,5,352,659, 5,248,807, 5,240,910, 5,198,548, 5,187,195, 5,082,838). Byvirtue of this activity, such compounds are considered to be useful forthe treatment of hypertension such as peripheral circulatory failure,heart disease such as angina pectoris, cardiomyopathy, arteriosclerosis,myocardial infarction, pulmonary hypertension, vasospasm, vascularrestenosis, Raynaud's disease, cerebral stroke such as cerebral arterialspasm, cerebral ischemia, late phase cerebral spasm after subarachnoidhemorrhage, asthma, bronchoconstriction, renal failure, particularlypost-ischemic renal failure, cyclosporine nephrotoxicity such as acuterenal failure, colitis, as well as other inflammatory diseases,endotoxic shock caused by or associated with endothelin, and otherdiseases in which endothelin has been implicated. As noted above, manyof the compounds, particularly the sulfonamide compounds, are potentendothelin antagonists, and, thus, are ideal clinical candidates. Forclinical use, stable formulations and suitable formulations for variousroutes of administration are needed.

Existing methods for making such sulfonamides are associated withcertain shortcomings. For example, certain steps in the syntheticpathway are known to result in dimerization of intermediates with theresultant decrease in yield and purity. Second, because the compoundsare hydrophobic, purification is difficult, typically, requiring theimpractical use of preparative HPLC or column chromatography. Finally,the existing methods are limited to the production of the hydrophobicfree sulfonamide, which sulfonamide is difficult to formulate intoaqueous based pharmaceutical compositions. Attempts to convert the freesulfonamide to useful salts of alkali metals using metal hydroxides ormethoxides may lead to decomposition of the compound.

Therefore, it is an object herein to provide formulations of compoundsthat have the ability to modulate the biological activity of one or moreof the endothelin peptides. It is another object to provide formulationsof compounds that have use as specific endothelin antagonists. It isalso an object to use formulations of compounds that specificallyinteract with or inhibit the interaction of endothelin peptides withET_(A) or ET_(B) receptors. Such formulations should be useful astherapeutic agents for the treatment of endothelin-mediated diseases anddisorders. Furthermore, there continues to be a need in the art for apractical, efficient method for making salts of desired sulfonamides.

SUMMARY OF THE INVENTION

Salts of Sulfonamide Compounds

Sulfonamide derivatives for use in the formulations and methods providedherein, and methods of preparing sulfonamide derivatives are provided.The sulfonamide derivatives are useful as endothelin receptorantagonists. Of interest are pharmaceutically acceptable derivatives,including salts, esters, acids and bases, solvates, hydrates andprodrugs of the sulfonamides. In particular, derivatives of neutralsulfonamide compounds that yield formulations of unexpectedly greaterstability than formulations containing the corresponding neutralcompounds are provided. Preferred are salts, particularly alkali metalsalts, and more preferably sodium salts, including salts prepared fromsodium compounds, including, but not limited to, sodium bicarbonate inwhich the resulting product is a sodium salt and disodium hydrogenphosphate in which the resulting compound is a sodium hydrogen phosphatesalt. The sodium salt of each compound is most preferred.

The salt derivatives include, but are not limited to, salts of alkalimetals and alkaline earth metals, including but not limited to sodiumsalts, potassium salts, lithium salts, calcium salts and magnesiumsalts; transition metal salts, such as zinc salts, copper salts, goldsalts and silver salts, and other metal salts, such as aluminum salts;cationic and polycationic counter ion salts, such as but not limited toammonium and substituted ammonium salts and organic amine salts, such ashydroxyalkylamines and alkylamines; salts of mineral acids, such as butnot limited to hydrochlorides and sulfates; salts of organic acids, suchas but not limited to, acetates lactates, malates, tartrates, citrates,ascorbates, succinates, butyrates valerates and fumarates. Alsocontemplated herein are the corresponding esters of any of the acids.

Among the preferred salts are: the salts of acetates, includingtrifluoroacetate, N,N′-dibenzylethylenediamine, chloroprocaine, choline,ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkyl amines, piperazine, tris(hydroxymethyl)aminomethane,aluminum, calcium, lithium, magnesium, potassium, sodium hydrogenphosphate, disodium phosphate, sodium, zinc, barium, gold, silver andbismuth. Alkali metal salts, particularly sodium salts, are preferredherein.

The sulfonamides from which the derivatives, particularly the salts,preferably sodium salts, are prepared have formula I:

Such sulfonamides include those described in U.S. Pat. Nos. 5,464,853,5,594,021, 5,591,761, 5,571,821, 5,514,691, 5,464,853, commonly ownedco-pending U.S. application Ser. No. 08/721,183, and commonly ownedInternational PCT application Publication Nos. WO 96/31492 and WO94/27979.

In certain embodiments, the sulfonamide salts are chosen with theproviso that the salt is not4-chloro-3-methyl-5-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole,sodium salt;N²-(3-cyanomethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide,sodium salt;N²-(3-acetyloxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide,sodium salt; orN²-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolyl-sulfamoyl)-2-thiopenecarboxamide,sodium salt.

In particular, sulfonamides of formula (I) are those in which Ar¹ is asubstituted or unsubstituted alkyl or is a five or six memberedsubstituted or unsubstituted aromatic or heteroaromatic ring,particularly 3- or 5-isoxazolyl and pyridazinyl, and also includingthiazolyl, including 2-thiazolyl, pyrimidinyl, including 2-pyrimidinyl,or substituted benzene groups, including aryloxy substituted benzenegroups or is a bicyclic or tricyclic carbon or heterocyclic ring. Ar¹is, in certain embodiments, selected from groups such as:

where R is selected from H, NH₂, halide, pseudohalide, alkyl,alkylcarbonyl, formyl, an aromatic or heteroaromatic group, alkoxyalkyl,alkylamino, alkylthio, arylcarbonyl, aryloxy, arylamino, arylthio,haloalkyl, haloaryl, carbonyl, in which the aryl and alkyl portions, areunsubstituted or substituted with any of the preceding groups, andstraight or branched chains of from about 1 up to about 10-12 carbons,preferably, 1 to about 5 or 6 carbons. R is preferably H, NH₂, halide,CH₃, CH₃O or another aromatic group.

Ar² is any group such that the resulting sulfonamide inhibits binding by50%, compared to binding in the absence of the sulfonamide, of anendothelin peptide to an endothelin receptor at a concentration of lessthan about 100 μM, except that Ar² is not phenyl or naphthyl when Ar¹ isN-(5-isoxazolyl) or N-(3-isoxazolyl) unless the isoxazole is a4-halo-isoxazole, a 4-higher alkyl (C₈ to C₁₅)-isoxazole, or thecompound is a 4-biphenyl that is unsubstituted at the 2 or 6 position onthe sulfonamide-linked phenyl group.

In particular, Ar² is a substituted or unsubstituted group selected fromamong groups, subject to the above proviso, including, but not limitedto, the following: naphthyl, phenyl, biphenyl, quinolyl, styryl,thienyl, furyl, isoquinolyl, pyrrolyl, benzofuryl, pyridinyl,thianaphthyl, indolyl, alkyl, and alkenyl. It is understood that thepositions indicated for substituents, including the sulfonamide groups,may be varied. Thus, for example, compounds herein encompass groups thatinclude thiophene-3-sulfonamides and thiophene-2-sulfonamides.

The sulfonamides are substituted or unsubstituted monocyclic orpolycyclic aromatic or heteroaromatic sulfonamides, such as benzenesulfonamides, naphthalene sulfonamides and thiophene sulfonamides.Particularly preferred sulfonamides are N-isoxazolyl sulfonamides. Moreparticularly preferred among such sulfonamides are those in which Ar² isa heterocycle that contains one ring, multiple rings or fused rings,typically two or three rings and one or two heteroatoms in the ring orrings.

In preferred sulfonamide derivatives, preferably sodium salts, Ar² isthienyl, furyl, pyrrolyl or a group, such as benzofuryl, thianaphthyl orindolyl, that is a derivative or analog, as described below, of athienyl, furyl or pyrrolyl group or a 4-biphenyl group, Ar¹ ispreferably N-(5-isoxazolyl) or N-(3-isoxazolyl). Of most interestherein, are salts, particularly sodium salts, including the sodium salt,of compounds in which Ar² is a phenylacetyl-substituted thienyl, furyl,pyrrolyl group. Preferred among these as salts, particularly sodiumsalts, are those in which Ar² is thienyl, furyl or pyrrolyl,particularly in which Ar² is substituted with phenylacetyl, and Ar¹ isisoxazolyl.

In certain embodiments, preferred salts are selected from among4-chloro-3-methyl-5-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole,sodium salt;N²-(3-cyanomethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide,sodium salt;N²-(3-acetyloxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide,sodium salt; andN²-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiopenecarboxamide,sodium salt.

Among the more preferred sulfonamide salts is the sodium salt ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenyl-acetyl]thiophene-3-sulfonamide,also referred to herein as4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole,sodium salt.

Sulfonamides

Also provided are sulfonamide compounds, and derivatives andformulations thereof, as described herein. The sulfonamide compounds areactive as endothelin receptor antagonists and provide enhancedtolerability relative to sulfonamides known in the art. Preferred amongthe sulfonamide compounds are those of formula:

where Ar¹ is isoxazolyl and Ar² has the formula:

or a pharmaceutically acceptable derivative, including alkali metalsalt, particularly sodium salt, thereof, wherein:

R³ and R⁴ are independently selected from the group consisting ofhydrogen, halo, cyano, cyanoalkyl, C(O)R⁴¹, alkyl, alkenyl, cycloalkyland aryl, or together form alkylene;

W is O, NH or CH₂;

R⁵, R⁶ and R⁷ are each independently selected as in (i) or (ii), withthe proviso that at most one of R⁵, R⁶ and R⁷ is hydrogen:

(i) R⁶ is hydrogen, unsubstituted alkyl, hydroxy, unsubstituted alkoxy,C(O)R⁴¹, carbamoyloxy or alkoxycarbonyloxy, and

R⁵ and R⁷ are each independently selected from hydrogen, unsubstitutedalkyl, hydroxy, C(O)R⁴¹, carbamoyloxy and alkoxycarbonyloxy; or

(ii) if at least one of R³ and R⁴ is not hydrogen, then any two may formalkylenedioxy, and the other is selected as in (i);

R⁴⁵ is selected from the group consisting of alkyl, C(O)R⁴¹, (CH₂)_(x)OHand CH(OH)(CH₂)_(x)CH₃ in which x is 0-6, S(O)_(n)R⁴¹ in which n is 0-2and C(═NR⁴³)R⁴¹;

R⁴¹ is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl,alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino,arylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylarylamino,arylsulfonylalkylamino or arylsulfonylarylamino; and

R⁴³ is selected from hydroxy, alkoxy, alkyl and aryl, wherein

R⁴¹ and R⁴³ are unsubstituted or substituted with one or moresubstituents selected from Y, which is alkoxy, halide, pseudohalide,carboxyl, alkoxycarbonyl, aryloxycarbonyl or hydroxy, with the provisothat the compound is notN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethylphenyl-aminocarbonyl)thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamide,N-(3,4-dimethyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)carbonyl]thiophene-3-sulfonamideorN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)-carbonyl]thiophene-3-sulfonamide.

In other embodiments, the sulfonamides are selected with the furtherproviso that the compound is notN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocarbonyl)-thiophene-3-sulfonamide,N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamideorN-(3,4-dimethyl-5-isoxazolyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide.

Thus, the sulfonamides provided herein are2-acyl-3-thiophenesulfonamides. The corresponding3-acyl-2-thiophenesulfonamides are also contemplated herein.Formulations and salts as described herein of the above compounds arealso provided.

Formulations of Sulfonamides and Sulfonamide Salts

Formulations of sulfonamide compounds, which have activity as endothelinantagonists, for administration to mammals, including humans, areprovided. In particular, formulations for parenteral, includingintramuscular, intravenous and subcutaneous administration, oraladministration, transdermal administration and other suitable routes ofadministration are provided. The formulations provide a means toconsistently deliver effective amounts of the compounds.

Of interest are formulations of pharmaceutically acceptable derivatives,including salts, esters, acids and bases, solvates, hydrates andprodrugs of the sulfonamides. In particular, derivatives of neutralsulfonamide compounds that yield formulations of greater stability thanformulations containing the corresponding neutral compounds areprovided. Preferred are salts, particularly alkali metal salts, and morepreferably sodium salts, including salts prepared from sodium compounds,including, but not limited to, sodium bicarbonate in which the resultingproduct is a sodium salt and disodium hydrogen phosphate in which theresulting compound is a sodium hydrogen phosphate salt. The sodium saltof each compound is most preferred.

The formulations are compositions suitable for administration by anydesired route and include solutions, suspensions, emulsions, tablets,dispersible tablets, pills, capsules, powders, dry powders for inhalers,sustained release formulations, aerosols for nasal and respiratorydelivery, patches for transdermal delivery and any other suitable route.The compositions should be suitable for oral administration, parenteraladministration by injection, including subcutaneously, intramuscularlyor intravenously as an injectable aqueous or oily solution or emulsion,transdermal administration and other selected routes.

Lyophilized powders of the sulfonamide derivatives, methods forpreparation thereof, and formulations containing reconstituted forms ofthe lyophilized powders are also provided. Vials and ampules andsyringes and other suitable vessels containing the powders are alsoprovided.

Also among the most preferred formulations for use in methods providedherein, are those that contain compounds that are ET_(A) selective,i.e., they interact with ET_(A) receptors at substantially lowerconcentrations (at an IC₅₀ at least about 10-fold lower, preferably100-fold lower) than they interact with ET_(B) receptors. In particular,compounds that interact with ET_(A) with an IC₅₀ of less than about 10μM, preferably less than 1 μM, more preferably less than 0.1 μM, butwith ET₅ with an IC₅₀ of greater than about 10 pM or compounds thatinteract with ET_(B) with an IC₅₀ of less than about 10 μM, preferablyless than 1 μM, more preferably less than 0.1 μM, but with ET_(A) withan IC₅₀ of greater than about 10 μM are preferred.

Preferred formulations also include compounds that are ET_(B) receptorselective or that bind to ET_(B) receptors with an IC₅₀ of less thanabout 1 μM. ET_(B) selective compounds interact with ET_(B) receptors atIC₅₀ concentrations that are at least about 10-fold lower than theconcentrations at which they interact with ET_(A) receptors.

The formulations provided herein are for administration by a selectedroute and contain effective concentrations ofpharmaceutically-acceptable salts of the above-noted compounds. Theformulations deliver amounts effective for the treatment ofhypertension, stroke, cardiovascular diseases, cardiac diseasesincluding myocardial infarction, pulmonary hypertension,erythropoietin-mediated hypertension, respiratory diseases, inflammatorydiseases, including asthma, bronchoconstriction, ophthalmologic diseasesincluding glaucoma and inadequate retinal perfusion, gastroentericdiseases, renal failure, endotoxin shock, menstrual disorders, obstetricconditions, wounds, anaphylactic shock, hemorrhagic shock, and otherdiseases in which endothelin mediated physiological responses areimplicated or that involve vasoconstriction or whose symptoms can beameliorated by administration of an endothelin antagonist or agonist,are also provided.

In one embodiment, the formulations are capsules and tablets containingthe sodium salt of a sulfonamide described herein. Preferredformulations are those that deliver amounts effective for the treatmentof hypertension or renal failure. The effective amounts andconcentrations are effective for ameliorating any of the symptoms of anyof the disorders.

In more preferred embodiments, the formulations are solid dosage formsor gels, preferably capsules or tablets. In a preferred embodiment, theformulations are capsules containing an effective amount, typicallyabout 10-100%, preferably about 50 to 95%, more preferably about 75-85%,most preferably about 80-85%, by weight, of one or more sodium hydrogenphosphate or sodium, preferably sodium, salts of one or more sulfonamidecompounds of formula I; about 0 to 25%, preferably 8-15%, of an diluentor a binder, such as lactose or microcrystalline cellulose; about 0 to10%, preferably about 3-7%, of a disintegrant, such as a modified starchor cellulose polymer, particularly a cross-linked sodium carboxymethylcellulose, such as crosscarmellose sodium (Crosscarmellose sodium NF isavailable commercially under the name AC—DI—SOL, FMC Corporation,Philadelphia, Pa.) or sodium starch glycolate; and 0-5%, preferably0.1-2%, of a lubricant, such a magnesium stearate, talc and calciumstearate. The disintegrant, such as crosscarmellose sodium or sodiumstarch glycolate, provides for rapid break-up of the cellulosic matrixfor immediate release of active agent following dissolution of coatingpolymer. In all embodiments, the precise amount of active ingredient andauxiliary ingredients can be determined empirically and is a function ofthe route of administration and the disorder that is treated. Solidforms for administration as tablets are also contemplated herein.

Preferred formulations are prepared from a sterile lyophilized powdercontaining a sodium salt of a sulfonamide. The lyophilized powders andmethods of preparing the powders are also provided herein.

In one embodiment, the compositions are provided in the form oflyophilized solids containing one or more sodium hydrogen phosphate orsodium, preferably sodium, salts of one or more sulfonamide compounds offormula I, and also contain one or more of the following:

a buffer, such as sodium or potassium phosphate, or citrate;

a solubilizing agent, such as LABRASOL (polyethylene glycol-8 capryliccapric glycerides sold by Gattefosse SA, France), dimethylsulfoxide(DMSO), bis(trimethylsilyl)acetamide, ethanol, propyleneglycol (PG), orpolyvinylpyrrolidine (PVP); and

a sugar or other such carbohydrate, such as sorbitol or dextrose(typically in the range of about 1%-20%, preferably about 5%-15%, morepreferably about 5%-10%).

For administration, the lyophilized powder is mixed (typically to yielda single dosage or multiple dosage formulation, about 100-500 mg,preferably 250 mg) with a suitable carrier, such as a phosphate bufferedsaline.

In other preferred embodiments, in which the formulations are designedfor parenteral administration, the compositions contain one or moresodium hydrogen phosphate or sodium, preferably sodium, salts of one ormore sulfonamide compounds of formula l; a buffer, such as sodium orpotassium phosphate, or citrate; and a sugar, such as sorbitol ordextrose. In a preferred embodiment described in detail herein, theformulations contain one or more sodium salts of the sulfonamidecompounds of formula I; a sodium phosphate buffer; and dextrose.Dextrose may be added in the form of a sterile dextrose solution, whichis readily available from suppliers known to those of skill in the art.

Methods of Use

Methods using such formulations for modulating the interaction of anendothelin peptide with ET_(A) and/or ET_(B) receptors are provided. Themethods are effected by contacting the receptors with one or more of theformulated pharmaceutically-acceptable salts of the sulfonamides,preferably formulated sodium salts of the sulfonamides, prior to,simultaneously with, or subsequent to contacting the receptors with anendothelin peptide.

Methods for inhibiting binding of an endothelin peptide to an endothelinreceptor are provided. These methods are practiced by contacting thereceptor with one or more of the formulations ofpharmaceutically-acceptable salts of the compounds provided hereinsimultaneously, prior to, or subsequent to contacting the receptor withan endothelin peptide.

Methods for treatment of endothelin-mediated disorders, including butnot limited to, hypertension, asthma, shock, ocular hypertension,glaucoma, inadequate retinal perfusion and other conditions that are insome manner mediated by an endothelin peptide, or for treatment ofdisorder that involve vasoconstriction or that are ameliorated byadministration of an endothelin antagonist or agonist are provided.

In particular, methods of treating endothelin-mediated disorders byadministering effective amounts of formulations ofpharmaceutically-acceptable salts of the sulfonamides, prodrugs or othersuitable derivatives of the sulfonamides are provided. In particular,methods for treating endothelin-mediated disorders, includinghypertension, cardiovascular diseases, cardiac diseases includingmyocardial infarction, pulmonary hypertension, erythropoietin-mediatedhypertension, respiratory diseases and inflammatory diseases, includingasthma, bronchoconstriction, ophthalmologic diseases, gastroentericdiseases, renal failure, endotoxin shock, menstrual disorders, obstetricconditions, wounds, anaphylactic shock, hemorrhagic shock, and otherdiseases in which endothelin mediated physiological responses areimplicated, by administering effective amounts of one or more of theformulations of pharmaceutically-acceptable salts of the compoundsprovided herein in pharmaceutically acceptable carriers are provided.Preferred methods of treatment are methods for treatment of hypertensionand renal failure.

More preferred methods of treatment are those in which the formulationscontain at least one compound that inhibits the interaction ofendothelin-1 with ET_(A) receptors at an IC₅₀ of less than about 10 μM,and preferably less than about 5 μM, more preferably less than about 1μM, even more preferably less than 0.1 μM, and most preferably less than0.05 μM. Other preferred methods are those in which the formulationscontain pharmaceutically-acceptable salts of one or more compounds thatis (are) ET_(A) selective or pharmaceutically-acceptable salts of one ormore compounds that is (are) ET_(B) selective. Methods in which thecompounds are ET_(A) selective are for treatment of disorders, such ashypertension; and methods in which the compounds are ET_(B) selectiveare for treatment of disorders, such as asthma, that requirebronchodilation.

In practicing the methods, effective amounts of formulations containingtherapeutically effective concentrations of pharmaceutically-acceptablesalts of the compounds formulated for oral, intravenous, local andtopical application for the treatment of hypertension, cardiovasculardiseases, cardiac diseases, including myocardial infarction, respiratorydiseases, including asthma, inflammatory diseases, ophthalmologicdiseases, gastroenteric diseases, renal failure,immunosuppressant-mediated renal vasoconstriction,erythropoietin-mediated vasoconstriction, endotoxin shock, anaphylacticshock, hemorrhagic shock, pulmonary hypertension, and other diseases inwhich endothelin mediated physiological responses are implicated areadministered to an individual exhibiting the symptoms of one or more ofthese disorders. The amounts are effective to ameliorate or eliminateone or more symptoms of the disorders.

Methods for the identification and isolation of endothelin receptorsubtypes are also provided. In particular, methods for detecting,distinguishing and isolating endothelin receptors using the disclosedcompounds are provided. In particular, methods are provided fordetecting, distinguishing and isolating endothelin receptors using thecompounds provided herein.

In addition, methods for identifying compounds that are suitable for usein treating particular diseases based on their preferential affinity fora particular endothelin receptor subtype are also provided.

Articles of manufacture containing packaging material, a formulationprovided herein, which is effective for ameliorating the symptoms of anendothelin-mediated disorder, antagonizing the effects of endothelin orinhibiting binding of an endothelin peptide to an ET receptor, in whichthe formulation contained within the packaging material includes acompound that has an IC₅₀ of less than about 10 μM, and a label thatindicates that the formulation is used for antagonizing the effects ofendothelin, treating an endothelin-mediated disorder, or inhibiting thebinding of an endothelin peptide to an ET receptor are provided.

Methods of Preparation

Also provided is a process of making an alkali metal salt of ahydrophobic free sulfonamide The process includes the steps ofdissolving the free sulfonamide in an organic solvent, washing thedissolved free sulfonamide with a saturated solution of a salt of thealkali metal, and recovering the alkali metal salt of the sulfonamidefrom the organic phase. A preferred organic solvent is ethyl acetate orTHF. Preferred alkali metals are sodium, potassium, calcium or magnesiumwith sodium being most preferred. In accordance with a preferredembodiment, the process uses saturated sodium bicarbonate or sodiumcarbonate as the alkali metal salt solution. Sodium bicarbonate is mostpreferred.

Recovery preferably includes the steps of drying the salt solution inorganic solvent, concentrating the salt, crystallizing the salt in oneor more organic, non-water miscible solvents and collecting thesulfonamide salt by filtration. Preferred organic, non-water misciblesolvents are dichloromethane and ether. The process provided herein canfurther include the step of purifying the sulfonamide salt afterrecovery.

An embodiment of the process is particularly useful for making4-chloro-3-methyl-5(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole,sodium salt;N²-(3-cyanomethyl-2,4,6-trimethylphenyl)-3(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide,sodium salt;N²-(3-acetyloxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide,sodium salt; andN²-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide,sodium salt.

The alkali metal salts of sulfonamides, particularly such salts providedby the present process, are provided. A preferred such sulfonamide saltis4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazol,sodium salt.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference.

As used herein, endothelin (ET) peptides include peptides that havesubstantially the amino acid sequence of endothelin-1, endothelin-2 orendothelin-3 and that act as potent endogenous vasoconstrictor peptides.

As used herein, an endothelin-mediated condition is a condition that iscaused by abnormal endothelin activity or one in which compounds thatinhibit endothelin activity have therapeutic use. Such diseases include,but are not limited to hypertension, cardiovascular disease, asthma,inflammatory diseases, ophthalmologic disease, menstrual disorders,obstetric conditions, gastroenteric disease, renal failure, pulmonaryhypertension, endotoxin shock, anaphylactic shock, or hemorrhagic shock.Endothelin-mediated conditions also include conditions that result fromtherapy with agents, such as erythropoietin and immunosuppressants, thatelevate endothelin levels.

As used herein an effective amount of a compound for treating aparticular disease is an amount that is sufficient to ameliorate, or insome manner reduce the symptoms associated with the disease. Such amountmay be administered as a single dosage or may be administered accordingto a regimen, whereby it is effective. The amount may cure the diseasebut, typically, is administered in order to ameliorate the symptoms ofthe disease. Typically, repeated administration is required to achievethe desired amelioration of symptoms.

As used herein, an endothelin agonist is a compound that potentiates orexhibits a biological activity associated with or possessed by anendothelin peptide.

As used herein, an endothelin antagonist is a compound, such as a drugor an antibody, that inhibits endothelin-stimulated vasoconstriction andcontraction and other endothelin-mediated physiological responses. Theantagonist may act by interfering with the interaction of the endothelinwith an endothelin-specific receptor or by interfering with thephysiological response to or bioactivity of an endothelin isopeptide,such as vasoconstriction. Thus, as used herein, an endothelin antagonistinterferes with endothelin-stimulated vasoconstriction or other responseor interferes with the interaction of an endothelin with anendothelin-specific receptor, such as ET_(A) receptors, as assessed byassays known to those of skill in the art.

The effectiveness of potential agonists and antagonists can be assessedusing methods known to those of skill in the art. For example,endothelin agonist activity can be identified by its ability tostimulate vasoconstriction of isolated rat thoracic aorta or portal veinring segments (Borges et al. (1989) “Tissue selectivity of endothelin”Eur. J. Pharmacol. 165:223-230). Endothelin antagonist activity can beassessed by the ability to interfere with endothelin-inducedvasoconstriction. Exemplary assays are set forth in the EXAMPLES. Asnoted above, the preferred IC₅₀ concentration ranges are set forth withreference to assays in which the test compound is incubated with the ETreceptor-bearing cells at 4° C. Data presented for assays in which theincubation step is performed at the less preferred 24° C. areidentified. It is understood that for purposes of comparison, theseconcentrations are somewhat higher than the concentrations determined at4° C.

As used herein, the biological activity or bioactivity of endothelinincludes any activity induced, potentiated or influenced by endothelinin vivo. It also includes the ability to bind to particular receptorsand to induce a functional response, such as vasoconstriction. It may beassessed by in vivo assays or by in vitro assays, such as thoseexemplified herein. The relevant activities include, but are not limitedto, vasoconstriction, vasorelaxation and bronchodilation. For example,ET_(B) receptors appear to be expressed in vascular endothelial cellsand may mediate vasodilation and other such responses; whereas ET_(A)receptors, which are endothelin-1-specific, occur on smooth muscle andare linked to vasoconstriction. Any assay known to those of skill in theart to measure or detect such activity may be used to assess suchactivity (see, e.g., Spokes et al. (1989) J. Cardiovasc. Pharmacol.13(Suppl. 5):S191-S192; Spinella et al. (1991) Proc. Natl. Acad. Sci.USA 88: 7443-7446; Cardell et al. (1991) Neurochem. Int. 18:571-574);and the Examples herein).

As used herein, bioavailability refers to the rate and extent ofabsorption. Methods for determining bioavailability are well known tothose of skill in the art. For example, bioavailability of any of thecompounds described herein can be determined empirically byadministration of the compound to an animal, followed by taking bloodsamples over time and measuring the blood concentration of the compound.In vivo half life (t_(½)) is defined as the time it takes for theconcentration of the compound in the blood to be reduced by one-half.Estimations of the area under the curve for intravenous administrationcan be used to estimate the area under the curve for oraladministration, yielding bioavailability data. See, e.q., Milo Gibal(1991) Biopharmaceutics and Pharmacology, 4th edition (Lea and Sediger).

As used herein, efficacy refers to the maximal effect that can beproduced by a compound. Efficacy can be determined by methods known tothose of skill in the art. For example, it can be determined by theproperties of the compound and its receptor-effector system and isreflected in the plateau of the concentration-effect curve. In vivoefficacy refers to efficacy which is determined in an animal model. Forexample, in vivo efficacy of the compounds described herein can bedetermined by amelioration of hypoxia-induced pulmonary hypertension inrat. In this context, in vivo efficacy refers to the ability of acompound to restore an elevated pulmonary artery pressure to a normalvalue. See, e.q., DiCarlo et al. (1995) Am. J. Physiol. 269:L690-L697.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as binding of endothelin to tissue receptors, in an assaythat measures such response.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

As used herein a sulfonamide that is ET_(A) selective refers tosulfonamides that exhibit an IC₅₀ that is at least about 10-fold lowerwith respect to ET_(A) receptors than ET_(B) receptors.

As used herein, a sulfonamide that is ET_(B) selective refers tosulfonamides that exhibit an IC₅₀ that is at least about 1 0-fold lowerwith respect to ET_(B) receptors than ET_(A) receptors.

As used herein, pharmaceutically-acceptable salts, esters, hydrates,solvates or other derivatives of the compounds include any such salts,esters and other derivatives that may be prepared by those of skill inthis art using known methods for such derivatization and that producecompounds that may be administered to animals or humans withoutsubstantial toxic effects and that either are pharmaceutically active orare prodrugs. Pharmaceutically-acceptable salts include, but are notlimited to, salts of alkali metals and alkaline earth metals, includingbut not limited to sodium salts, potassium salts, lithium salts, calciumsalts and magnesium salts; transition metal salts, such as zinc salts,copper salts and aluminum salts; polycationic counter ion salts, such asbut not limited to, ammonium and substituted ammonium salts and organicamine salts, such as hydroxyalkylamines and alkylamines; salts ofmineral acids, such as but not limited to hydrochlorides and sulfates,salts of organic acids, such as but not limited to, acetates, lactates,malates, tartrates, citrates, ascorbates, succinates, butyrate, valerateand fumarates. Also contemplated herein are the corresponding esters.

Preferred pharmaceutically-acceptable salts include, but are not limitedto, N,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia,diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine, tris(hydroxymethyl)aminomethane,aluminum, calcium, lithium, magnesium, potassium, sodium hydrogenphosphate, disodium phosphate, sodium, zinc, barium, gold, silver andbismuth salts. Sodium salts, particularly the sodium salt of each of thecompound, are most preferred herein.

As used herein, reference to “sodium salts” refers to salts of anysodium compounds in which the counter ion includes Na⁺ and can includeother ions, such as HPO₄ ²⁻; reference to a “sodium salt” (rather thansodium salts) refers specifically to a salt in which Na⁺ is the counterion.

As used herein, treatment means any manner in which the symptoms of acondition, disorder or disease are ameliorated or otherwise beneficiallyaltered. Treatment also encompasses any pharmaceutical use of thecompositions herein, such as use as contraceptive agents.

As used herein, substantially pure means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis and high performance liquid chromatography (HPLC), usedby those of skill in the art to assess such purity, or sufficiently puresuch that further purification would not detectably alter the physicaland chemical properties, such as enzymatic and biological activities, ofthe substance. Methods for purification of the compounds to producesubstantially chemically pure compounds are known to those of skill inthe art. A substantially chemically pure compound may, however, be amixture of stereoisomers. In such instances, further purification mightincrease the specific activity of the compound.

As used herein, biological activity refers to the in vivo activities ofa compound or physiological responses that result upon in vivoadministration of a compound, composition or other mixture. Biologicalactivity, thus, encompasses therapeutic effects and pharmaceuticalactivity of such compounds, compositions and mixtures.

As used herein, increased stability of a formulation means that thepercent of active component present in the formulation, as determined byassays known to those of skill in the art, such as high performanceliquid chromatography, gas chromatography, and the like, at a givenperiod of time following preparation of the formulation is significantlyhigher than the percent of active component present in anotherformulation at the same period of time following preparation of theformulation. In this case, the former formulation is said to possessincreased stability relative to the latter formulation.

As used herein, a prodrug is a compound that, upon in vivoadministration, is metabolized or otherwise converted to thebiologically, pharmaceutically or therapeutically active form of thecompound. To produce a prodrug, the pharmaceutically active compound ismodified such that the active compound will be regenerated by metabolicprocesses. The prodrug may be designed to alter the metabolic stabilityor the transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacodynamic processes and drug metabolism in vivo, those of skill inthis art, once a pharmaceutically active compound is known, can designprodrugs of the compound (see, eg., Nogrady (1985) Medicinal Chemistry ABiochemical Approach, Oxford University Press, New York, pages 388-392).For example, succinyl-sulfathiazole is a prodrug of4-amino-N-(2-thiazoyl)benzenesulfonamide (sulfathiazole) that exhibitsaltered transport characteristics.

As used herein, acid isostere means a group that is significantlyionized at physiological pH. Examples of suitable acid isosteres includesulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl,arylsulfonylcarbamoyl or heteroarylsulfonylcarbamoyl.

As used herein, halo or halide refers to the halogen atoms; F, Cl, Brand I.

As used herein, pseudohalides are compounds that behave substantiallysimilar to halides. Such compounds can be used in the same manner andtreated in the same manner as halides (X^(—), in which X is a halogen,such as Cl or Br). Pseudohalides include, but are not limited tocyanide, cyanate, thiocyanate, selenocyanate and azide.

As used herein, haloalkyl refers to a loweralkyl radical in which one ormore of the hydrogen atoms are replaced by halogen including, but notlimited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl andthe like.

As used herein, alkyl means an aliphatic hydrocarbon group that is astraight or branched chain preferably having about 1 to 12 carbon atomsin the chain. Preferred alkyl groups are loweralkyl groups which arealkyls containing 1 to about 6 carbon atoms in the chain. Branched meansthat one or more loweralkyl groups such as methyl, ethyl or propyl areattached to a linear alkyl chain. The alkyl group may be unsubstitutedor independently substituted by one or more groups, such as, but notlimited to: halo, carboxy, formyl, sulfo, sulfino, carbamoyl, amino andimino. Exemplary alkyl groups include methyl, ethyl and propyl.

As used herein the term lower describes alkyl, alkenyl and alkynylgroups containing about 6 carbon atoms or fewer. It is also used todescribe aryl groups or heteroaryl groups that contain 6 or fewer atomsin the ring. Loweralkyl, lower alkenyl, and lower alkynyl refer tocarbon chains having less than about 6 carbons. In preferred embodimentsof the compounds provided herein that include alkyl, alkenyl, or alkynylportions include loweralkyl, lower alkenyl, and lower alkynyl portions.

As used herein, alkenyl means an aliphatic hydrocarbon group containinga carbon—carbon double bond and which may be straight or branchedchained having from about 2 to about 10 carbon atoms in the chain.Preferred alkenyl groups have 2 to about 4 carbon atoms in the chain.Branched means that one or more loweralkyl or lower alkenyl groups areattached to a linear alkenyl chain. The alkenyl group may beunsubstituted or independently substituted by one or more groups, suchas, but not limited to: halo, carboxy, formyl, sulfo, sulfino,carbamoyl, amino and imino. Exemplary alkenyl groups include ethenyl,propenyl and butenyl.

As used herein, alkynyl means an aliphatic hydrocarbon group containinga carbon—carbon triple bond and which may be straight or branched havingabout 2 to 10 carbon atoms in the chain. Branched means that one or moreloweralkyl, alkenyl or alkynyl groups are attached to a linear alkynylchain. An exemplary alkynyl group is ethynyl.

As used herein, aryl means an aromatic monocyclic or multicyclichydrocarbon ring system containing from 3 to 15 or 16 carbon atoms,preferably from 5 to 10. Aryl groups include, but are not limited togroups, such as phenyl, substituted phenyl, naphthyl, substitutednaphthyl, in which the substituent is loweralkyl, halogen, or loweralkoxy. Preferred aryl groups are lower aryl groups that contain lessthan 7 carbons in the ring structure.

As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. are usedas is generally understood by those of skill in this art. For example,as used herein alkyl refers to saturated carbon chains that contain oneor more carbons; the chains may be straight or branched or includecyclic portions or be cyclic. As used herein, alicyclic refers to arylgroups that are cyclic.

As used herein, cycloalkyl refers to saturated cyclic carbon chains;cycloalkenyl and cycloalkynyl refer to cyclic carbon chains that includeat least one unsaturated double or triple bond, respectively. The cyclicportions of the carbon chains may include one ring or two or more fusedrings.

As used herein, cycloalkenyl means a non-aromatic monocyclic ormulticyclic ring system containing a carbon—carbon double bond andhaving about 3 to about 10 carbon atoms. Exemplary monocycliccycloalkenyl rings include cyclopentenyl or cyclohexenyl; preferred iscyclohexenyl. An exemplary multicyclic cycloalkenyl ring isnorbornylenyl. The cycloalkenyl group may be independently substitutedby one or more halo or alkyl.

As used herein, “haloalkyl” refers to a loweralkyl radical in which oneor more of the hydrogen atoms are replaced by halogen including, but notlimited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl andthe like.

As used herein, “haloalkoxy” refers to RO— in which R is a haloalkylgroup.

As used herein, “carboxamide” refers to groups of formula R_(p)CONH₂ inwhich R is selected from alkyl or aryl, preferably loweralkyl or loweraryl and p is 0 or 1.

As used herein, “alkylaminocarbonyl” refers to —C(O)NHR in which R ishydrogen, alkyl, preferably loweralkyl or aryl, preferably lower aryl.

As used herein “dialkylaminocarbonyl” as used herein refers to —C(O)NR′Rin which R′ and R are independently selected from alkyl or aryl,preferably loweralkyl or loweraryl; “carboxamide” refers to groups offormula NR′COR.

As used herein, “alkoxycarbonyl” as used herein refers to —C(O)OR inwhich R is alkyl, preferably loweralkyl or aryl, preferably lower aryl.

As used herein, “alkoxy” and “thioalkoxy” refer to RO— and RS—, in whichR is alkyl, preferably loweralkyl or aryl, preferably lower aryl.

As used herein, “aminocarbonyl” refers to —C(O)NH₂.

As used herein, alkylenedioxy means an —O—alkyl—O— group in which thealkyl group is as previously described. A replacement analog ofalkylenedioxy means an alkylenedioxy in which one or both of the oxygenatoms is replaced by a similar behaving atom or group of atoms such as,S, N, NH, Se. An exemplary replacement alkylenedioxy group isethylenebis(sulfandiyl). Alkylenethioxyoxy is —S—alkyl—O—, —O—alkyl—S—and alkylenedithioxy is —S— alkyl—S—.

As used herein, heteroaryl means an aromatic monocyclic or fused ringsystem in which one or more of the carbon atoms in the ring systemis(are) replaced by an element(s) other than carbon, for examplenitrogen, oxygen or sulfur. Preferred cyclic groups contain one or twofused rings and include from about 3 to about 7 members in each ring.Similar to “aryl groups”, the heteroaryl groups may be unsubstituted orsubstituted by one or more substituents. Exemplary heteroaryl groupsinclude pyrazinyl, pyrazolyl, tetrazolyl, furyl, (2- or 3-)thienyl,(2-,3- or 4-)pyridyl, imidazoyl, pyrimidinyl, isoxazolyl, thiazolyl,isothiazolyl, quinolinyl, indolyl, isoquinolinyl, oxazolyl and1,2,5-oxadiazolyl. Preferred heteroaryl groups include 5 to 6-memberednitrogen-containing rings, such as pyrimidinyl.

As used herein, alkoxycarbonyl means an alkyl—O—CO— group. Exemplaryalkoxycarbonyl groups include methoxy- and ethoxycarbonyl.

As used herein, carbamoyl means —CONH₂. As with all groups describedherein, these groups may be unsubstituted or substituted. Substitutedcarbamoyl includes groups such as —CONY²Y³ in which Y² and Y³ areindependently hydrogen, alkyl, cyano(loweralkyl), aryalkyl,heteroaralkyl, carboxy(loweralkyl), carboxy(aryl substitutedloweralkyl), carboxy(carboxy substituted loweralkyl), carboxy(hydroxysubstituted loweralkyl), carboxy(heteroaryl substituted loweralkyl),carbamoyl(loweralkyl), alkoxycarbonyl(loweralkyl) or alkoxycarbonyl(arylsubstituted loweralkyl), provided that only one of Y² and Y³ may behydrogen and when one of Y² and Y³ is carboxy(loweralkyl), carboxy(arylsubstituted loweralkyl), carbamoyl(loweralkyl),alkoxycarbonyl(loweralkyl) or alkoxycarbonyl(aryl substitutedloweralkyl) then the other of Y² and Y³ is hydrogen or alkyl. Preferredfor Y² and Y³ are independently hydrogen, alkyl, cyano(loweralkyl),aryalkyl, heteroaralkyl, carboxy(loweralkyl), carboxy(aryl substitutedloweralkyl) and carbamoyl(loweralkyl).

As used herein, any corresponding N-(4-halo-3-methyl-5-isoxazolyl),N-(4-halo-5-methyl-3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyl),N-(4-halo-5-methyl-3-isoxazolyl), N-(4-halo-3-methyl-5-isoxazolyl),N-(4,5-dimethyl-3-isoxazolyl) derivative thereof refers to compounds inwhich Ar² is the same as the compound specifically set forth, but Ar¹ isN-(4-halo-3-methyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl),N-(3,4-dimethyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl),N-(4-halo-3-methyl-5-isoxazolyl), or N-(4,5-dimethyl-3-isoxazolyl) inwhich halo is any halide, preferably Cl or Br.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, (1972) Biochem.11:942-944).

A. Salts of Sulfonamide Compounds

In the embodiments described in detail herein, salts, preferably sodiumsalts, of sulfonamide compounds for use in the formulations and methodsprovided herein are those in which Ar¹ is an isoxazole and the compoundsare represented by the formulae II:

in which R¹ and R² are either (i), (ii) or (iii) as follows:

(i) R¹ and R² are each independently selected from H, NH₂, NO₂, halide,pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsulfinyl,alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl,haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl,arylcarbonyl, formyl, substituted or unsubstituted amido, substituted orunsubstituted ureido, in which the alkyl, alkenyl and alkynyl portionscontain from 1 up to about 14 carbon atoms and are either straight orbranched chains or cyclic, and the aryl portions contain from about 4 toabout 16 carbons, except that R² is not halide or pseudohalide; or,

(ii) R¹ and R² together form —(CH₂)_(n), where n is 3 to 6; or,

(iii) R¹ and R² together form 1,3-butadienyl, and with the above provisothat Ar² is not phenyl or naphthyl when Ar¹ is N-(5-isoxazolyl) orN-(3-isoxazolyl) unless the isoxazole is a 4-halo-isoxazole, a 4-higheralkyl (C₈ to C₁₅)-isoxazole, or the compound is a 4-biphenylsulfonamidethat is unsubstituted at the 2 or 6 position on the sulfonamide-linkedphenyl group.

In preferred embodiments herein, R¹ and R² are each selectedindependently from among alkyl, lower alkenyl, lower alkynyl, lowerhaloalkyl, halide, pseudohalide or H, except that R² is not halide.

In certain embodiments, the sulfonamides are chosen with the provisothat the compound is not4-chloro-3-methyl-5(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole,sodium salt;N²-(3-cyanomethyl-2,4,6-trimethylphenyl)-3(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide,sodium salt;N²-(3-acetyloxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide,sodium salt; orN²-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiopenecarboxamide,sodium salt.

In certain embodiments described in detail herein, Ar² is a 4-biphenylor is a single ring heterocycle, particularly a 5-membered ring, or is afused bicyclic or tricyclic heterocycle that contains one or more,particularly one, heteroatom selected from S, O and NR⁴², in the ring,where R⁴² contains up to about 30 carbon atoms, preferably 1 to 10, morepreferably 1 to 6 and is selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, C(O)R¹⁵ and S(O)_(n)R¹⁵ in which n is 0-2;R¹⁵ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl; R⁴² and R¹⁵are unsubstituted or are substituted with one or more substituents eachselected independently from Z, which is hydrogen, halide, pseudohalide,alkyl, alkoxy, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁶, CO₂R¹⁶, SH,S(O)_(n)R¹⁶ in which n is 0-2, NHOH, NR¹²R¹⁶, NO₂, N₃, OR¹⁶, R¹²NCOR¹⁶and CONR¹²R¹⁶; R¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl; R¹², which is selected independently from R⁴² and Z, isselected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,C(O)R¹⁷ and S(O)_(n)R¹⁷ in which n is 0-2; and R¹⁷ is hydrogen, alkyl,alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl or cycloalkynyl; each of R⁴², R¹², R¹⁵ and R¹⁶may be further substituted with the any of the groups set forth for Z.

In preferred embodiments herein, R⁴² is aryl, such as phenyl or alkylphenyl, hydrogen or loweralkyl.

Thus, in the compounds provided herein Ar² includes thienyl, furyl andpyrrolyl, benzofuryl, benzopyrrolyl, benzothienyl, benzo[b]furyl,benzo[b]thienyl, and indolyl (benzo[b]pyrrolyl) and 4-biphenyl, and Ar¹is preferably N-(5-isoxazolyl) or N-(3-isoxazolyl). The sulfonamides areN-isoxazolyl sulfonamides and the compounds have formula III:

in which X is S, O or NR¹¹ in which R¹¹ contains up to about 30 carbonatoms, preferably 1 to 10, more preferably 1 to 6 and is selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁵ andS(O)_(n)R¹⁵ in which n is 0-2; R¹⁵ is hydrogen, alkyl, alkenyl, alkynyl,aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl; R¹¹ and R¹⁵ are unsubstituted or aresubstituted with one or more substituents each selected independentlyfrom Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl,alkynyl, aryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁶, CO₂R¹⁶, SH, S(O)_(n)R¹⁶ inwhich n is 0-2, NHOH, NR¹²R¹⁶, NO₂, N₃, OR¹⁶, R¹²NCOR¹⁶ and CONR¹²R¹⁶;R¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R¹², whichis selected independently from R¹¹ and Z, is selected from hydrogen,alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁷ andS(O)_(n)R¹⁷ in which n is 0-2; and R¹⁷ is hydrogen, alkyl, alkenyl,alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl or cycloalkynyl; each of R¹¹, R¹², R¹⁵ and R¹⁶ may befurther substituted with the any of the groups set forth for Z, and R¹¹is preferably hydrogen, aryl, such as phenyl or alkyl phenyl,loweralkyl; or the compounds are 4-biphenylsulfonamides in which Ar¹ ispreferably N-(5-isoxazolyl) or N-(3-isoxazolyl.

Among the embodiments described in detail herein, Ar² is thienyl, furyl,pyrrolyl or a group that is a derivative or analog, as described below,of a thienyl, furyl or pyrrolyl group, including benzo[b] derivativessuch as a benzo[b]thienyl, Ar¹ is N-(5-isoxazolyl) or N-(3-isoxazolyl).Ar² has the formula IV:

in which X is O, S or NR¹¹, where R¹¹ is as defined above;

that can be substituted at any or all positions or is an analog orderivative of the groups of formula (IV) in which the substituents formfused aromatic, aliphatic or heterocyclic rings; and R⁸, R⁹ and R¹⁰ areeach independently selected as follows from (i) or (ii):

(i) R⁸, R⁹ and R¹⁰, which each contain hydrogen or up to about 50 carbonatoms, generally up to about 30, more generally 20 or fewer, are eachindependently selected from hydrogen, halide, pseudohalide, alkyl,alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁸,(OAc)C═CHR¹⁸, CO₂R¹⁸, SH, (CH₂)_(r)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(S)(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)(CH═CH)_(S)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(S)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH═CH)_(S)(CH₂)_(n)R¹⁸, C═N(OH) (CH₂)_(r)R¹⁸,(CH₂)_(r)(CH═CH)_(S)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸,C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)R¹⁸,S(O)_(m)R¹⁸ in which m is 0-2, s, n and r are each independently 0 to 6,preferably 0-3, HNOH, NR¹⁸R¹⁹, NO₂, N₃, OR¹⁸, R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸,in which R¹⁹ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, alkoxy, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, C(O)R²⁰, S(O)_(n)R²⁰ in which n is 0-2; andR¹⁸ and R²⁰ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, alkylaryl, heterocyclyl, alkoxy, aryloxy,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and any ofthe groups set forth for R⁸, R⁹ and R¹⁰ are unsubstituted or substitutedwith any substituents set forth for Z, which is hydrogen, halide,pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy,heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,OH, ON, C(O)R²¹, CO₂R²¹, SH, S(O)_(n)R²¹ in which n is 0-2, NHOH,NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ and CONR²²R²¹; R²² is selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,C(O)R²³ and S(O)_(n)R²³ in which n is 0-2; and R²¹ and R²³ are.independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl, with the proviso that if R⁸ is NR¹⁸R¹⁹, OR¹⁸, R¹⁹NCOR¹⁸and CONR¹⁹R¹⁸ CO₂R¹⁸, (CH₂)_(r)NH(CH═CH)_(S)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(S)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸,C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH₂)_(n)R¹⁸ or (CH₂)_(r)R¹⁸ andR¹⁸ is an aryl group containing 5 or 6 members, then the aryl group hasat least two substituents, and preferably one substituent at the2-position relative to the linkage to the thienyl, furyl or pyrrolyl;

(ii) any two of R⁸, R⁹ and R¹⁰ with the carbon to which each is attachedform an aryl, aromatic ring, heteroaromatic ring, carbocyclic orheterocyclic ring, which is saturated or unsaturated, containing fromabout 3 to about 16 members, preferably 3 to about 10 members, morepreferably 5 to 7 members that is substituted with one or moresubstituents, each substituent is independently selected from Z; theother of R⁸, R⁹ and R¹⁰ is selected as in (i); and the heteroatoms areNR¹¹, O, or S, with the proviso that Ar² is not5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo[b]furyl,5-halo-3-loweralkylbenzo[b]pyrrolyl.

In the embodiments provided herein, the alkyl, alkynyl and alkenylportions of each listed substituent are straight or branched chains,acyclic or cyclic, and preferably have from about 1 up to about 10carbons; in more preferred embodiments they have from 1-6 carbons. Thearyl, alicyclic, aromatic rings and heterocyclic groups can have from 3to 16, generally, 3-7, more often 5-7 members in the rings, and may besingle or fused rings. The ring size and carbon chain length areselected up to an amount that the resulting molecule binds and retainsactivity as an endothelin antagonist or agonist, such that the resultingcompound inhibits binding by 50%, compared to binding in the absence ofthe sulfonamide, of an endothelin peptide to an endothelin receptor at aconcentration of less than about 100 μM.

In preferred embodiments of interest herein, R⁹ and R¹⁰ are hydrogen,halide or methyl, more preferably hydrogen or halide, and R⁸ is selectedfrom CO₂R¹⁸, (CH₂)_(r)C(O)(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH),(CH₂)_(n)R¹⁸,C═N(OH)(CH₂)_(r)R¹⁸, (CH₂)_(r)C(O)(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH═CH)_(s)(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH)_(s)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(n)R¹⁸, with the proviso that if R⁸ isCO₂R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸ or (CH₂)_(r)R¹⁸ and R¹⁸ is phenyl, thephenyl group is substituted at least two positions, and preferably, atleast one of those positions is ortho.

In the preferred compounds, R¹⁸ is aryl or heteroaryl, preferably having5 or 6 members in the ring, more preferably phenyl or pyrimidinyl, mostpreferably phenyl.

In the most preferred compounds herein, R¹⁸ is phenyl, which issubstituted at more than one position, and most preferably at least onesubstituent is at the ortho position, R⁹ and R¹⁰ are each hydrogen,halide or loweralkyl, preferably hydrogen, and R⁸ is C(O)NHR¹⁸,C(O)CH₂R¹⁸, (CH₂)R¹⁸, with the proviso that if R⁸ is C(O)NHR¹⁸, then thephenyl group must have at least two substituents, preferably one of thesubstituents is in the ortho position.

In other preferred embodiments, Ar² is a benzo[b]thienyl, benzo[b]furyl,or indolyl (benzo[b]pyrrolyl), with the proviso that the benzene ring issubstituted and the substituents are other than 5-halo, 3-loweralkyl.Preferred substituents on the benzene ring, include, but are not limitedto, one or more selected from alkylenedioxy, particularlymethylenedioxy, preferably 3,4-methylenedioxy, ethylenedioxy, aryl,particularly phenyl, dimethylamino, diethylamino, benzyl, alkoxy,particularly lower alkoxy, such as methoxy and ethoxy, halide, andalkyl, preferably loweralkyl.

In the preferred compounds herein, R² is preferably, selected from amongalkyl, lower alkenyl, lower alkynyl, lower haloalkyl or H; and R¹ ishalide or loweralkyl, and more preferably, R¹ is bromide or chloride,methyl or ethyl. In the most active compounds provided herein, asevidenced by in vitro binding assays, R¹ is bromide or chloride. For usein vivo R¹ is preferably chloride.

In most preferred embodiments herein, the formulations contain sodiumsalts of the above compounds in which R⁸ is a phenylacetyl. Of thecompounds described herein, those that inhibit or increase anendothelin-mediated activity by about 50% at concentrations of less thanabout 10 μM are preferred. More preferred are those that inhibit orincrease an endothelin-mediated activity by about 50% at concentrationsof less than about 1 μM, more preferably less than about 0.1 μM, evenmore preferably less than about 0.01 μM, and most preferably less thanabout 0.001 μM. It is noted that, as described below, the IC₅₀concentration determined in the in vitro assays is a non-linear functionof incubation temperature. The preferred values recited herein refer tothe assays that are performed at 4° C. When the assays are performed at24° C., somewhat higher (see, Table 1) IC₅₀ concentrations are observed.Accordingly, the preferred IC₅₀ concentrations are about 10-fold higher.

Also among the most preferred compounds for use in methods providedherein, are those that are ET_(A) selective, i.e., they interact withET_(A) receptors at substantially lower concentrations (at an IC₅₀ atleast about 10-fold lower, preferably 100-fold lower) than they interactwith ET_(B) receptors. In particular, compounds that interact withET_(A) with an IC₅₀ of less than about 10 μM, preferably less than 1 μM,more preferably less than 0.1 μM, but with ET_(B) with an IC₅₀ ofgreater than about 10 μM or compounds that interact with ET_(B) with anIC₅₀ of less than about 10 μM, preferably less than 1 μM, morepreferably less than 0.1 μM, but with ET_(A) with an IC₅₀ of greaterthan about 10 μM are preferred.

Preferred compounds also include compounds that are ET_(B) receptorselective or that bind to ET_(B) receptors with an IC₅₀ of less thanabout 1 μM. ET_(B) selective compounds interact with ET_(B) receptors atIC₅₀ concentrations that are at least about 10-fold lower than theconcentrations at which they interact with ET_(A) receptors. In thesecompounds, R² is selected from among alkyl, lower alkenyl, loweralkynyl, lower haloalkyl, halide or H; and R¹ is halide or loweralkyl,and in preferred embodiments, R¹ is bromide or chloride, preferablychloride; R⁹ and R¹⁰ are selected independently from hydrogen,loweralkyl, preferably methyl or ethyl, or halide, and R⁸, which is thesubstituent at the 5-position (see, e.g., formulae III and IV), is arylor a heterocycle, particularly phenyl and isoxazolyl, which areunsubstituted or substituted with Z, which is preferably loweralkyl orhalide.

1. Ar² is a thiophene, pyrrole, furan, benzo[b]thiophene, indolyl(benzo[b]pyrrole), or benzo[b]furan

Among the sulfonamide salts provided herein are salts of compoundsrepresented by the formula V:

in which R¹ and R² are either (i), (ii) or (iii) as follows:

(i) R¹ and R² are each independently selected from H, NH₂, NO₂, halide,pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,alkoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsulfinyl,alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl,aminocarbonyl, arylaminocarbonyl, haloalkyl, haloaryl, alkoxycarbonyl,alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido,substituted or unsubstituted ureido, in which the alkyl, alkenyl andalkynyl portions are either straight or branched chains that containfrom 1 up to about 10 carbon atoms, and the aryl portions contain fromabout 4 to about 14 carbons, except the R² is not halide, pseudohalideor higher alkyl; or,

(ii) R¹ and R² together form —(CH₂)_(n), where n is 3 to 6; or,

(iii) R¹ and R² together form 1,3-butadienyl; and

X is S, O or NR¹¹ in which R¹¹ contains up to about 30 carbon atoms,preferably 1 to 10, more preferably 1 to 6 and is selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁵ andS(O)_(n)R¹⁵ in which n is 0-2; R¹⁵ is hydrogen, alkyl, alkenyl, alkynyl,aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl; R¹¹ and R¹⁵ are unsubstituted or aresubstituted with one or more substituents each selected independentlyfrom Z, which is hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl,alkynyl, aryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁶, CO₂R¹⁶, SH, S(O)_(n)R¹⁶ inwhich n is 0-2, NHOH, NR¹²R¹⁶, NO₂, N₃, OR¹⁶, R¹²NCOR¹⁶ and CONR¹²R¹⁶;R¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R¹², whichis selected independently from R¹¹ and Z, is selected from hydrogen,alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁷ andS(O)_(n)R¹⁷ in which n is 0-2; and R¹⁷ is hydrogen, alkyl, alkenyl,alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl or cycloalkynyl; each of R¹¹, R¹², R¹⁵ and R¹⁶ may befurther substituted with the any of the groups set forth for Z, and R¹¹is preferably hydrogen, aryl, such as phenyl or alkyl phenyl,loweralkyl; and R⁸, R⁹ and R¹⁰, which each contain hydrogen or up toabout 50 carbon atoms, generally up to about 30, more generally 20 orfewer, are each independently selected as described above, and morepreferably from (i) or (ii) as follows:

(i) R⁹ and R¹⁰ are selected from hydrogen, halide, pseudohalide, alkyl,alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁸,(OAc)C═CHR¹⁸, CO₂R¹⁸, SH, (CH₂)_(r)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(S)(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)(CH═CH)_(S)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(S)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH═CH)_(S)(CH₂)_(n)R¹⁸, C═N(OH) (CH₂)_(r)R¹⁸,(CH₂)_(r)(CH═CH)_(S)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸,C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)R¹⁸,S(O)_(m)R¹⁸ in which m is 0-2, s, n and r are each independently 0 to 6,preferably 0-3, HNOH, NR¹⁸R¹⁹, NO₂, N₃, OR¹⁸, R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸,in which R¹⁹ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, alkoxy, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, C(O)R²⁰, S(O)_(n)R²⁰ in which n is 0-2; andR¹⁸ and R²⁰ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, alkylaryl, heterocyclyl, alkoxy, aryloxy,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;

R⁸ is selected from C(O)R¹⁸, (OAc)C═CHR¹⁸, CO₂R¹⁸,(CH₂)_(r)C(O)(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH)_(S)(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)(CH═CH)_(S)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(S)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH═CH)_(S)(CH₂)_(n)R¹⁸, C═N(OH)(CH₂)_(r)R¹⁸,(CH₂)_(r)(CH═CH)_(S)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸,C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)R¹⁸, inwhich m is 0-2, s, n and r are each independently 0 to 6, preferably0-3, in which R¹⁸ is aryl, preferably phenyl, with the proviso that, ifR⁸ is (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)R¹⁸, particularly if r is 0 and/or nis 0, and R¹⁸ is aryl, particularly phenyl, then R¹⁸ must have two ormore substituents, with preferably at least one ortho substituent;

where any of the groups set forth for R⁸, R⁹ and R¹⁰ are unsubstitutedor substituted with any substituents set forth for Z, which is hydrogen,halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy,heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,OH, CN, C(O)R²¹, CO₂R²¹, SH, S(0)_(n)R²¹ in which n is 0-2, NHOH,NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ and CONR²²R²¹; R²² is selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,C(O)R²³ and S(O)_(n)R²³ in which n is 0-2; and R²¹ and R²³ areindependently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl; or

(ii) any two of R⁸, R⁹ and R¹⁰ form an aryl, aromatic ring,heteroaromatic ring, carbocyclic or heterocyclic ring, which issaturated or unsaturated, containing from about 3 to about 16 members,preferably 3 to about 10 members, more preferably 5 to 7 members that issubstituted with one or more substituents, each substituent beingindependently selected from Z; the other of R⁸, R⁹ and R¹⁰ is selectedas from the groups set forth for R⁹ and R¹⁰ in (i); and the heteroatomsare NR¹¹, 0, or S, with the proviso that Ar² is not5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo[b]furyl,5-halo-3-loweralkylbenzo[b]pyrrolyl.

In these embodiments, Ar² is, thus, represented by the formulae (IVA andIVB):

that can be substituted at any or all positions or is an analog ofcompounds of formula (IV) in which the substituents form fused aromatic,aliphatic or heterocyclic rings; and in which X is NR¹¹, O, or S, andR¹¹, which is hydrogen or contains up to about 30 carbon atoms,preferably 1 to 10, more preferably 1 to 6, and is selected as definedabove. R⁸, R⁹, R¹⁰ are selected as described above.

In the embodiments provided herein, when R⁸, R⁹ and R¹⁰ are selected asin (i), above, R⁸ is preferably selected from among(CH₂)_(r)C(O)(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)NH(CH₂)_(n)R¹⁸, C═N(OH)(CH₂)_(r)R¹⁸,(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH═CH)_(s)(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)R¹⁸, with the proviso that if R⁸ is(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, or(CH₂)_(r)R¹⁸, and R¹⁸ is phenyl, the phenyl group is substituted atleast two positions, and preferably, at least one of those positions isortho.

In preferred of these compounds, R¹⁸ is aryl or heteroaryl, preferablyhaving 5 or 6 members in the ring, more preferably phenyl orpyrimidinyl, most preferably phenyl. R⁹ and R¹⁰ are preferably hydrogen,halide, loweralkyl, or halo loweralkyl.

The more preferred compounds provided herein are compounds in which thealkyl, alkynyl and alkenyl portions are straight or branched chains,acyclic or cyclic, and have from about 1 up to about 10 carbons; incertain of the more preferred embodiments they have from 1-6 carbons,and they can have fewer than 6 carbons. The aryl, homocyclic andheterocyclic groups can have from 3 to 16, generally, 3-7, more often5-7 members in the rings, and may be single or fused rings. The ringsize and carbon chain length are selected such that the resultingmolecule exhibits activity as an endothelin antagonist or agonist asevidenced by In vitro or in vivo tests, particularly the testsexemplified herein.

In any of the above preferred embodiments: R¹ and R² are preferablyselected independently from alkyl, lower alkenyl, lower alkynyl, lowerhaloalkyl, halide, pseudohalide and H, except that R² is not halide orpseudohalide, and in preferred embodiments is also not higher alkyl.

In preferred embodiments: X is S, O, NR¹¹ in which R¹¹ is aryl,hydrogen, or loweralkyl, preferably, a substituted or unsubstitutedaryl, particularly phenyl, preferably unsubstituted or substituted withloweralkyl or halogen hydrogen or loweralkyl; R¹ is hydrogen, halide,pseudohalide, loweralkyl or lower haloalkyl, most preferably halide; R²is hydrogen, loweralkyl or lower haloalkyl.

The aryl groups are unsubstituted or is substituted with groups such asalkyl, alkoxy, alkoxyalkyl, halogen, alkylenedioxy, particularlymethylenedioxy, amino, nitro and other such groups. The alkylsubstituents are preferably loweralkyl, more preferably containing 1-3carbons.

In more preferred embodiments, two of R⁹ and R¹⁰ are hydrogen, halide orloweralkyl and R⁸ is C(O)NHR¹⁸ or C(O)CH₂R¹⁸ in which R¹⁸ is a phenylgroup that is substituted at least two positions, most preferably atleast one substituent at the ortho position and also 3,4 or 4,5alkylenedioxy substituents. In more preferred of these embodiments X isS.

In all embodiments, R¹ is preferably halide, H, CH₃ or C₂H₅, and R² isH, CH₃, C₂H₅, C₂F₅ or CF₃. In yet more preferred embodiments, R¹preferably Br, Cl or CH₃; R² is H, CH₃, C₂H₅, or CF₃.

In other embodiments two of R⁸, R⁹ and R¹⁰ form a ring so that Ar2 isbenzo[b]thienyl, benzo[b]furyl, or indolyl, with the proviso that thereis one or more substituents and they are other than 5-halo and3-loweralkyl, and the other of R⁸, R⁹ and R¹⁰ is selected from aryl,(CH₂)_(r)R¹⁸, C(O)R¹⁸, CO₂R¹⁸, NR¹⁸R¹⁹, SH, S(O)_(n)R¹⁸ in which n is0-2, HNOH, NO₂, N₃, OR¹⁸, R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸. Ar² may be furthersubstituted with any of the groups set forth for R⁸, R⁹ and R¹⁰, and arepreferably selected from among alkyl, alkoxy, alkoxyalkyl, aryl,alkylaryl, aminoalkyl, arylamino, aryl-substituted amino, and NR¹¹.

In embodiments in which ET_(B) antagonists are desired, it is preferredthat R⁸ and R¹⁰ are H or loweralkyl and R⁹ includes heterocyclic oraromatic ring of preferably from 3 to 14, more preferably, 5 to 7,members in the ring. In particular, if X is S, R⁸ and R¹⁰ are H orloweralkyl, and R⁹, includes an aryl group, particularly a substitutedphenyl, such as a 2-loweralkyl substituent. The aryl portion issubstituted with groups such as alkyl, alkoxy, alkoxyalkyl, halogen,alkylenedioxy, particularly methylenedioxy, amino, nitro and other suchgroups. The alkyl substituents are preferably loweralkyl, morepreferably containing 1-3 carbons.

If X is NR¹¹, then R¹¹ is aryl, particularly unsubstituted phenyl orsubstituted phenyl, such as isopropylphenyl.

Other preferred compounds, which are ET_(B) active, are those in whichAr² has formula IVB in which R⁹ is aryl or Z-substituted aryl,particularly phenyl, and Z is loweralkyl or loweralkoxy.

In all embodiments of all of the compounds herein R¹ is preferablyhalide or loweralkyl, most preferably Br, and the compounds are, withreference to formulae IV, 2- or 3-sulfonamides, particularly thiophenesulfonamides. In certain embodiments provided herein, Ar² is abenzo[b]thienyl, benzo[b]furyl or indolyl (benzo[b]pyrrolyl) group andthe compounds provided herein are preferably benzo[b]thienyl-,benzo[b]furyl- or indolylsulfonamides. Benzo[b]thienyl, benzo[b]furyland indolyl 2- or 3-sulfonamides are among the compounds preferredherein. The benzo[b]thienyl, benzo[b]furyl and indolyl 2- or3-sulfonamides provided herein are selected with the proviso that thebenzene group has at least one substituent and that substituent is otherthan 5-halo and 3-loweralkyl.

Compounds of particular interest include salts, particularly sodiumsalts, of formula III in which Ar² is a phenyl-, benzothienyl,benzofuryl or indolyl [benzopyrrolyl] group or in which Ar² is asubstituted phenylaminocarbonylthienyl, substitutedphenylaminocarbonylfuryl, substituted aminocarbonylpyrrolyl group inwhich there are at least two substituents or Ar² is phenylacetylthienyl,phenylacetylfuryl, or phenylacetylpyrrolyl, or is anacetoxystyrylthienyl, acetoxystyrylfuryl or acetoxystyrylpyrrolyl group.

The most preferred compounds provided herein are the salts of thecompounds that have an IC₅₀ for ET_(A) receptors in the assaysexemplified herein less than 0.1 μM, more preferably less than 0.01 μM,and more preferably less than 0.001 (see, e.g., Table 1 forrepresentative experimental results), when measured at 4° C., asdescribed in the Examples. When measured at 24° C., the IC₅₀concentrations are somewhat higher (2- to 10-fold; see, Table 1 for somecomparative values).

Among the preferred compounds of interest herein are the salts of thosein which Ar² has formula VI:

in which M is (CH₂)_(m)C(O)(CH₂)_(m), (CH₂)_(m)C(O)NH(CH₂)_(r),(CH₂)_(m)(CH═CH)(CH₂)_(r), (CH₂)_(m)C(O)(CH₂)_(s)NH(CH₂)_(r),(CH₂)_(m)(CH═CH)(CH₂)_(r), C═N(OH)(CH₂)_(r),(CH₂)_(m)C(O)(CH═CH)_(s)NH(CH₂)_(r), CH(OH)(CH₂)_(r),CH(CH₃)C(O)(CH₂)_(r), CH(CH₃)C(O)(CH₂)_(m)(CH═CH)(CH₂)_(r), (CH₂)_(r),(CH₂)_(r)O, C(O)O, in which m,s and r are each independently 0 to 6,preferably 0 to 3, more preferably M is (CH₂)_(m)C(O)(CH₂)_(r),(CH₂)_(m)C(O)NH(CH₂)_(r), (CH₂)_(m)(CH═CH)(CH₂)_(r),(CH₂)_(m)C(O)(CH₂)_(s)NH(CH₂)_(r), (CH₂)_(m)(CH═CH)(CH₂)_(r),C═N(OH)(CH₂)_(r), CH(OH)(CH₂)_(r), (CH₂)_(r), (CH₂)_(r)O, C(O)O;

R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected from (i) or(ii) as follows:

(i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected fromamong H, OH, NHR³⁸, CONR³⁸R³⁹, NO₂, cyano, halide, pseudohalide, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino,alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl,alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenyl sulfinyl,alkenylsulfonyl, alkoxycarbonyl, arylaminocarbonyl, alkylaminocarbonyl,aminocarbonyl, (alkylaminocarbonyl)alkyl, carboxyl, carboxyalkyl,carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl,acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl,(acetoxy)alkoxy, (hydroxy)alkoxy and formyl; or

(ii) at least two of R³¹, R³², R³³, R³⁴ and R³⁵, which substituteadjacent carbons on the ring, together form alkylenedioxy,alkylenethioxyoxy or alkylenedithioxy (i.e. —O—(CH₂)_(n)—O—,—S—(CH₂)_(n)—O—, —S—(CH₂)_(n)—S—, where n is 1 to 4, preferably 1 or 2,)which is unsubstituted or substituted by replacing one or more hydrogenswith halide, loweralkyl, loweralkoxy or halo loweralkyl, and the othersof R³¹, R³², R³³, R³⁴ and R³⁵ are selected as in (i); and

R³⁸ and R³⁹ are each independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocyclyl, arylalkyl,arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl,and is preferably hydrogen, loweralkyl, loweralkoxy and lowerhaloalkyl,with the proviso that when M is (CH₂)_(m)C(O)NH(CH₂)_(r), then at leasttwo of R³¹, R³², R³³, R³⁴ and R³⁵ are not hydrogen.

M is most preferably selected from

In general, however, in all of these compounds in which Ar² has formulaV or VI or in which R⁸ includes an aryl group, regardless of theselection of M,it is preferred that the aryl substituent have more thanone substituent or at least one substituent in the ortho position. Arylis preferably phenyl that is preferably substituted at the orthoposition and, more preferably at least one additional position,particularly 4 and 6, or adjacent positions, such as 3,4 or 4,5 when thesubstituents are linked to form an alkylenedioxy (or analog thereof inwhich one or both oxygens is(are) replaced with S.

In all compounds, at least one of R³¹ and R³⁵ is other than hydrogen.

In more preferred compounds, M is C(O)CH₂, C(O)NH, —CH═CH—,CH₂CH₂C(O)(CH)₂, CH₂CHC(O)CH₂, and most preferably has formula VIl:

in which W is CH₂ or NH.

M is even more preferably selected from among:

in which R⁴⁰ is preferably hydrogen, alkyl, alkoxy, alkoxyalkyl,haloalkyl, and more preferably loweralkyl, loweralkoxy, or haloloweralkyl, and is more preferably hydrogen or loweralkyl, particularlymethyl or ethyl, and is most preferably hydrogen.

In preferred compounds R³¹, R³², R³³, R³⁴ and R³⁵ are selected from (i)or (ii):

(i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected fromloweralkyl, haloloweralkyl, phenyl, alkoxy,loweralkylsulfonylaminoloweralkyl, cyanoloweralkyl, acetyl,loweralkoxycarbonyl, cyano, OH, acetoxyloweralkyl, hydroxy loweralkyl,acetoxy loweralkoxy or loweralkoxycarbonyl; or

(ii) R³² and R³³ or R³³ and R³⁴ form alkylenedioxy, preferablymethylenedioxy, and the others of R³, R³², R³³, R³⁴ and R³⁵ are selectedas in (i).

In preferred embodiments, R³¹, R³³, R³⁵ are other then hydrogen and arepreferably loweralkyl or lower alkoxy, or R³¹ or R³⁵ is other thanhydrogen, preferably loweralkyl or lower alkoxy, and R³² and R³³ or R³³and R³⁴ form methylenedioxy.

In all embodiments, preferred substituents also can be determined byreference to Table 1, which sets forth exemplary compounds. Preferredcompounds are those of Table 1 that have the highest activities, andpreferred substituents are those on the compounds with the highestactivities.

TABLE 1 COMPOUND ET_(A) (μM)* ET_(B) (μM)*N-(4-bromo-3-methyl-5-isoxazolyl)-5-bromothio- 0.314 2.26phene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(2′-thienyl)thio- 5.1 0.363phene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxythio-0.103 3.46 phene-2-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)benzofuran-2-sulfona- 5.22 38.4 mideN-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide 3.13 —N-(4-bromo-3-methyl-5-isoxazolyl)-5-phenylfuran-2- 0.857 2.43sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)furan-2-sulfona- 0.75 88.1mide N-(4-bromo-3-methyl-5-isoxazolyl)-2,5- 0.46 36.5dimethylfuran-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenthio)furan- 5.0 7.02-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-1-(phenyl)pyrrole- 18.18.7 2-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-1-(4′- 11.4 0.166isopropylphenyl)pyrrole-2-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)1-(4′- 0.838 0.211 isopropylphenyl)pyrrole-3-sulfonamide(4-bromo-3-methyl-5-isoxazolyl)-1-(4′- 9.17 7.84biphenyl)pyrrole-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)2-thiophenesulfon- 0.095 ± 0.07 27.7 ±15.0 amide N-(4-bromo-5-methyl-3-isoxazolyl)thiophene-2-sul- 0.211 27.3fonamide N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-3-sul- 0.135 23.4fonamide 5-(3-isoxazolyl)-N-(3-methyl-5-isoxazolyl)-2-thio- 5.6 6.7phenesulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-pyridyl)thio-3.84 2.70 phene-2-sulfonamideN-(4-Bromo-3-methyl-5-isoxazolyl)-4,5-dibromothio- 0.281 2.58phene-2-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-5-chloro-3- 0.961.63 methylbenzo[b]thiophene-2-sulfonamideN-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4- 0.311 2.57chlorobenzamidomethyl)thiophene-2-sulfonamideN-(4-Bromo-3-methyl-5-isoxazolyl)-4- 0.383 —benzenesulfonylthiophene-2-sulfonamide4-bromo-5-chloro-N-(4-Bromo-3-methyl-5- 0.359 2.67isoxazolyl)-thiophene-2-sulfonamideN-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dimethylthio- 0.0956 7.8phene-3-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-4,5-dichlorothio-˜0.45 ˜4.9 phene-2-sulfonamideN-(4-Bromo-3-methyl-5-isoxazolyl)-4-bromo-2,5- ˜0.28 10.4dichlorothiophene-3-sulfonamideN-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dichlorothio- ˜0.39 2.62phene-3-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-5-{3-[1-methyl-˜6.7 ˜0.36 5-(trifluoromethyl)pyrazolyl]}thiophene-2-sulfonamideN-(4-Bromo-3-methyl-5-isoxazolyl)-5- 0.570 0.333benzenesulfonylthiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2- 0.0208 98.1(carbomethoxy)thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl-5-phenylthiophen-2-sul- 2.55 1.29 fonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(N- 0.0054 18.8phenylaminocarbonyl)thiophene-3-sulfonamideN-(4-bromo-5-methyl-3-isoxazolyl)-2-(N- — —phenylaminocarbonyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(N- — —phenylaminocarbonyl)thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene- 2.64 >˜1003-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl))-2-(carbomethoxy)thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-(N- 0.0182 ˜170phenylaminocarbonyl)thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-(carbomethoxy)thio- 0.367 —phene-3-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thio-˜0.6 ˜67 phene-3-sulfonamide N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-0.002 2.12 methoxyphenyl)aminocarbonyl]thiophene-3-sulfona- mideN-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(3- 0.003 5.86methoxyphenyl)aminocarbonyl]thiophene-3-sulfona- mideN-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(2- 0.0116 13.2methoxyphenyl)aminocarbonyl]thiophene-3-sulfona- mideN-(4-Bromo-3-methyl-5-isoxazolyl)-2-(N- 0.013 12.7benzylaminocarbonyl)thiophene-3-sulfonamideN-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4- 0.0016 0.849ethylphenyl)aminocarbonyl]thiophene-3-sulfonamideN-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4- 0.0376 0.912biphenyl)aminocarbonyl]thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-3-methoxythiophene-2- 2.5 45.5 sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4- 3.23 0.0855ethylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-phenylthio- 0.0547 11.1phene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenylthio-0.224 1.17 phene-2-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)benzo[b]thiophene-2- 7.22 11.1 sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-phenylthio- — — phene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(N- — —phenylaminocarbonyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-benzylthio- — — phene-2-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxythio- — —phene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4′- 1.6 0.3isopropylphenyl))thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-4-(4′- 5.5 1.3isopropylphenyl))thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4′- 5.6 0.51propylphenyl))thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[-(4-tolulyl- <0.01** 1.67**aminocarbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4- <0.01** 1.13**isopropylphenyl)aminocarbonyl]thiophene-3-sulfona- mideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-t- 0.011** 2.82**butylphenyl)aminocarbonylthiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(4- 0.044** 2.84**butylphenyl)aminocarbonylthiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-sec- ˜0.008** 1.76**butylphenyl)aminocarbonyl]thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-methylbenzo[b]thio- 0.167 16.6phene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2- 0.0486 3.5methylbenzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2- 0.0067 5.13ethylbenzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-n- 0.0182 ˜1benzylbenzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2- 0.0226 ˜3butylbenzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-i- 0.005 5.7propylbenzo[b]thiophene-3-sulfonamide 0.03^(†) 10.7^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-2-n- 0.024 7.95propylbenzo[b]thiophene-3-sulfonamide 0.074^(†) 16.6^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4- 0.048^(†) 1.1^(†)ethylbenzyl)benzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4- 0.0015 ± 0.0014 0.324 ± 0.78(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfon- 0.0074 ± 0.0011^(†)0.939 ± 0.262^(†) amide N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-0.013^(†) 1.2^(†) trimethoxybenzyl)-benzo[b]-thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-ethyl-5- 1.89 ± 0.431^(†) 54.3 ±2.6^(†) methylbenzo[b]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methy- 0.011 ± 0.005^(†)0.936 ± 0.095^(†) lenedioxy)benzyl]benzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy- 0.021 ± 0.017^(†)2.94 ± 1.32^(†) benzyl)benzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzo[b]thien- 16^(†) 0.80^(†)2-yl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-0.051^(†) 1.5^(†) methoxybenzyl)benzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxozolyl)-2-(2- 0.19^(†) 2.2^(†)methoxybenzyl)-benzo[b]thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-(4- 0.21^(†) 4.7^(†)chlorobenzyl)benzo[b]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(4- 0.041^(†) 1.3^(†)dimethylaminobenzyl)benzo[b]thiophene-3-sulfona- 0.014 0.477 mideN-(4-chloro-3-methyl-5-isoxazolyl)-2- 0.15^(†) 22^(†)ethylbenzo[b]furan-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-phenylben- 0.932^(†) 46.8^(†)zo[b]thiophene sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-6-methoxy-2- ˜2^(est) ^(†) 2.39^(†)[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3- sulfonamideN-(4-chloro-5-methyl-3-isoxazolyl)-2-[3,4-(methyl- 0.0055^(†) 0.364^(†)enedioxy)benzyl]benzo[b]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2- 0.631 53.2methoxycarbonylthiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-4-(4- 0.962^(†) 0.435^(†)propylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3- 0.0801^(†) 3.68^(†)(phenylthio)thiophene-2-sulfonamide N-(3,4-dimethyl-5-isoxazolyl))-3-0.163 >100 (phenylaminocarbonyl)thiophene-2-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-tolyl)amino- 0.00116 2.93carbonyl]thiophene-3-sulfonamide 0.0105^(†) 14^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4- 8.69 0.363methoxyphenyl)thiophene-2-sulfonamide 26.3^(†) 2.4^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3- 3.26 0.776methoxyphenyl)thiophene-2-sulfonamide 23.4^(†) 4.7^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thio- 4.49 0.380phene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-methylthio-0.651 7.15 phene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(phenethyl)thio- 0.16 10.77phene-2-sulfonamide 0.676^(†) 37.2^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-4-(phenethyl)thio- 6.64 3.97phene-2-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-[(4-methylphenyl)-0.00336 11.3 aminocarbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethyl-4- 1.40 ˜100phenylthiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2- 0.18816.0 [(methyl)phenylaminocarbonyl]thiophene-3-sulfona- mideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(α- 0.337 9.37hydroxybenzyl)thiophene-3-sulfonamideN-(4-bromo-5-methyl-3-isoxazolyl)-5-(4- 7.10 0.3593methylphenyl)thiophene-2-sulfonamide 15.8^(†) 0.25^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-phenylthio- 3.53 0.417phene-2-sulfonamide 36.6^(†) 2.4^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-[4- 6.39 0.0835(trifluoromethyl)phenyl]thiophene-2-sulfonamide 6.31^(†) .282^(†)N,N′-bis{3-[(4-bromo-3-methyl-5- 0.0692 0.290isoxazolyl)aminosulfonyl)thien-2-yl} urea 0.295^(†) 1.19^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-2- 0.160 44.1(hydroxymethyl)thiophene-3-sulfonamide 1.55^(†) —N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2- 3.46 0.529formylphenyl)thiophene-3-sulfonamide 12.31^(†) 1.28 ± 0.71^(†)N,N′-bis{3-[3,4-dimethyl-5- 1.01 ± 1.03 3.7 ± 2.7isoxazolyl)aminosulfonyl]thien-2-yl}urea 2.7^(†) 5.9^(†)N-(3,4-dimethyl-5-isoxazolyl))-2-[(3- 0.214 5.34methoxyanilino)methyl]thiophene-3-sulfonamide 0.933^(†) 7.7^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3- 0.537 1.07aminophenyl)thiophene-2-sulfonamide 1.44^(†) 2.63^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5- 0.794 12.0bis(triflouromethyl)phenyl]thiophene-2-sulfonamide 5.9^(†) 15.5^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3,3- 1.12 24.0dimethylbutyn-1-yl)thiophene-2-sulfonamide 7.24^(†) 35.5^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2- 0.381 1.097methoxyphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thio- 0.432 0.313phene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3- 0.062^(†)>100^(†) carboxyphenyl)aminocarbonyl]thiophene-3-sulfona- mideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[2- 0.21^(†) 20^(†)carboyxylphenyl)aminocarbonyl]-thiophene-3-sulfon- amideN-(4-bromo-3-methyl-5-isoxazolyl)-2- 0.84^(†) >100^(†)(aminocarbonyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(5- 0.97^(†) 3.9^(†)dimethylamino-1-naphthyl)sulfonyl- aminocarbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2- 17^(†) 0.21^(†)thienyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4- 0.017^(†) 9.8^(†)methylenedioxyphenyl)aminocarbonyl]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4- 0.0073^(†) 6.0^(†)methylenedioxy)phenoxycarbonyl]thiophene-3-sulfo- namideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(3,4- 0.50^(†) 79^(†)methylenedioxy)phenyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(3,4- 8.1^(†) 3.2^(†)methylenedioxy)benzyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthio- 1.6^(†) 39^(†)phene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-tolyl)thio-15^(†) 4.2^(†) phene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4- 0.27^(†) 7.7^(†)methylenedioxy)benzyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4- 2.0^(†) 15^(†)methylenedioxy)benzoyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2- 0.013^(†) 38^(†)hydroxyphenyl)aminocarbonyl]thiophene-3-sulfona- mideN-(3,4-dimenthyl-5-isoxazolyl)-2-[3,4- 6.1^(†) >˜50^(†)(methylenedioxy)phenoxycarbonyl]thiophene-3-sul- fonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethylthien-2- 24^(†) 7.7^(†)yl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-0.089^(†) 37^(†) methylenedioxy)benzoyl]aminocarbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- 0.0065^(†)7.4^(†) (methylenedioxy)phenoxycarbonyl]thiophene-3-sul- fonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(1- 29^(†) 5.6^(†)pentynyl)thiophene-2-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-5-(5-ethylthien-2- 12^(†) 0.71^(†)yl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-0.0091^(†) 5.5^(†) methylenedioxy)phenylacetyl]thiophene-3-sulfona- mideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4- 0.087^(†) 5.9^(†)(methylenedioxy)phenoxycarbonylamino]thiophene- 3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4- 13^(†) 0.76^(†)methylenedioxy)phenoxymethyl]thiophene-3-sulfona- mideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[trans-(3,4- 0.14^(†) 1.4^(†)methylenedioxy)cinnamyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(1-naphthyl)- 14^(†) 1.4^(†)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3- 26^(†)4.5^(†) nitrophenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4- 0.57^(†) 1.3^(†)methylenedioxy)phenylureido]thiophene-3-sulfona- mideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4- 0.021^(†) 6.5^(†)(methylenedioxy)phenylacetyl]thiophene-3-sulfona- mideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4- >100^(†) 17^(†)methyoxycarbonylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4- >100^(†) 31^(†)carboxyphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4- 28^(†) 8.6^(†)tolyl)aminocarbonyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(2- 32^(†) 7.5^(†)methyfuranyl)thiophene-2-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- .42^(†) 12^(†)(methylenedioxy)benzyloxycarbonyl]thiophene-3-sul- fonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-(3,4- .23^(†) 6.2^(†)methylenedioxyphenyl)ethoxycarbonyl-3-sulfona- mideN-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4-(3,4- 20^(†) >˜100^(†)methylenedioxybenzyl)piperazin-1-yl]carbonyl}thio- phene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-aminothio- 14^(†) 6.2^(†)phene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5- 12^(†) 9.0^(†)(benzyloxymethyl)thiophene-2-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-cyano-1- 2.1^(†) 27^(†)[(3,4-methylenedioxy)phenyl]acetyl}thiophene-3-sul- fonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4- 0.21^(†) 9.2^(†)methylenedioxy)phenethyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3- 1.4^(†) 60^(†)dimethylamino)phenoxycarbonyl]thiophene-3-sulfon- amideN-(4-bromo-3-methyl-5-isoxazolyl)-1-methylindole-2- 77^(†) ˜100^(†)sulfonamide N-(4-chloro-3-methyl-5-isoxozolyl-2- 0.44^(†) 34^(†)(cyclohexyloxycarbonyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[β-hydroxy(3,4- 0.053^(†) 16^(†)methylenedioxy)phenylethyl]thiophene-3-sulfona- mideN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxyl-1- 0.59^(†) 104^(†)methylidole-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-1.37^(†) — oxacyclohexyl)oxycarbonyl]thiophene-3-sulfonamideN-2-[3,4-(methylenedioxy)phenylacetyl]thiophene-3- 1.8^(†) 32.5^(†)sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-{2-[3,4-(methyl- — —enedioxy)phenyl]acetyl}thiophene-3-sulfonamide oximeN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4- 31.3^(†) 14.7^(†)tolyl)aminocarbonyl]-1-methylindole-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4- 0.023^(†) 15^(†)methoxyphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-1-[3,4-(methyl- 5.29^(†) 18.6^(†)enedioxy)benzyl]indole-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4- 122^(†) 9.7^(†)methylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy- 0.043^(†) 10.1^(†)phenyl)acetyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4- 1.64^(†) 22.8^(†)methylphenoxy)methyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4- 1.2^(†) 15^(†)methylphenoxy)methyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-trans- 0.94^(†) 0.66^(†)styryl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl- 0.347^(†) 9.4^(†)phenethyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl- 0.198^(†) 9.13^(†)phenyl)acetyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3- 0.030^(†) 19.1^(†)methoxyphenyl)acetyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl- 6.1^(†) 2.09^(†)phenethyl)-5-(4-tolyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4- 4.69^(†) 1.56^(†)methylbenzyl)-5-(4-tolyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-trans- 6.9^(†) 1.58^(†)styryl)-5-(4-tolyl)thiophene-2-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[β,β-(ethylene- 0.128^(†) 2.09^(†)dioxy)-3,4-(methylenedioxy)phenethyl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[β-(dimethyl- 20.9^(†) ˜100^(†)amino)-3,4-(methylenedioxy)phenethyl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-{α-hydroxy- 2.5^(†) 30^(†)[3,4-(methylenedioxy)phenyl]acetyl}thiophene-3-sul- fonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(5-methyl-3- 0.056^(†) 92^(†)isoxazolyl)aminocarbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-hydroxyl-6- 0.066^(†) 81.3^(†)pyridazinyl)aminocarbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-acetyl-4,5- 0.010^(†) 31.6^(†)(methylenedioxy)phenyl]aminocarbonyl}thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-{[3,4- 0.513^(†) 9.6^(†)(methylenedioxy)phenoxy]methyl}thiophene-2-sulfo- namideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4- 0.26^(†) 0.413^(†)methyl)(cinnamyl)] thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2[(4,5- 0.55^(†) —dimethoxy-2-methoxycarbonylphenyl)aminocar-bonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methyl- 0.13^(†) —1,3,4-thiadiazol-5-yl)aminocarbonyl]thiophene-3-sul- fonamideN-(4-chloro-3-methyl-5-isoxazolyl)2-{[4,5-dimethoxy- 3.80^(†) —2,4,5-dimethoxy-2-methoxycar-bonyl)phenyl]phenylaminocarbonyl}thiophene-3-sul- fonamideN-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-carboxyl- 1.43^(†) —4,5-(methylenedioxy)phenyl]aminocarbonyl}thio- phene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4- 0.236^(†) 18^(†)(methylenedioxy)phenethyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4- 0.218^(†) 10^(†)(methylenedioxy)-trans-styryl]thiophene-2-sulfona- mideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)- 0.106^(†) 40.1^(†)phenethyl]thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-{[2-acetyl-4,5- 0.032^(†) —(methylenedioxy)phenyl]aminocarbonyl}thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-methoxy-2- 0.027^(†) 0.14^(†)methylphenyl)aminocarbonyl]thiophene-3-sulfona- mideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[{2-cyano-4,5- 0.0039^(†) 12.2^(†)dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfon- amideN-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetylphenyl)- 0.0027^(†)29.2^(†) thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylene- 0.0273^(†) 12.2^(†)dioxy)phenylacetyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4- 0.158^(†) 63.1^(†)dimethoxyphenyl)aminocarbonyl)thiophene-3-sulfon- amideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6- 0.023^(†) 43.7^(†)pyridyl)aminocarbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-hydroxy-4- .006^(†) —methylphenyl)aminocarbonyl]thiophene-3-sulfona- mideN-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-cyano-4,5- 0.0034^(†) 40.4^(†)(methylenedioxy)phenyl]aminocarbonyl}thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- 0.0030^(†) 355^(†)(methylenedioxy)phenylaminocarbonyl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2- 0.011^(†) 61^(†)carboxamido-4,5-dimethoxyphenylamino- carbonyl)thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-(2,4- 0.0027^(†) 17.4^(†)dimethylphenylacetyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl- 0.0004^(†) 4.8^(†)phenylacetyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4- 0.0008^(†**) 3.6^(†)dimethylphenylacetyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- 0.0073^(†) 9.2^(†)(methylenedioxy)]phenylaminocarbonyl-3-thio- phenesulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- 0.0032^(†) 9^(†)(methylenedioxy)phenylacetyl]thiophene-3-sulfona- mideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- 0.0045^(†) 25.7^(†)(methylenedioxy)-6-(2-acetoxyethyl)phenylamino-carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- 0.0056^(†) 16.8^(†)(methylenedioxy)-6-(2-hydroxyethyl)phenylaminocarbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl- 0.045^(†) 17.7^(†)phenylacetyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5- 0.007^(†) 18^(†)dimethylphenylacetyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2- 0.0068^(†) 19.8^(†)methanesulfonylaminomethyl)-4,5-(methylenedioxy)phenylaminocarbonyl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-cyanomethyl- 0.0038^(†) 25^(†)4,5-(methylenedioxy)-6-cyanomethyl]-phenylaminocarbonyl-3-thiophenesulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-hyroxyproyl- 0.0073^(†) 8.3^(†)4,5-(methylenedioxy)phenylaminocarbonyl]thio- phene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-methyl-4,5- ˜0.1^(†**) ˜6^(†**)(methylenedioxy)cinnamyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-methyl-4,5- ˜0.1^(†**) ˜5^(†**)(methylenedioxy)phenethyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-{[2-propyl-4,5- ˜0.2^(†**) 1.5^(†**)(methylenedioxy)phenoxy]methyl}thiophene-2-sul- fonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- ˜0.02^(†)** ˜18^(†)(methylenedioxy)-6-(2-acetoxyethoxy)]phenylamino-carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- ˜0.01^(†)** ˜18^(†)(methylenedioxy)-6-(2-hydroxyethoxy)phenyl-aminocarbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-cyano-4,5- ˜0.3^(†)** ˜0.7^(†)(methylenedioxy)phenylacetyl]thiophene-3-sulfona- mideN-(4-chloro-3-methyl-5-isoxazolyl)-2-{2- 0.009^(†) 13.8^(†)[(dimethylamino)carbonylmethyl]-4,5-(methylene-dioxy)phenylaminocarbonyl}thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- 0.794^(†) 6.49^(†)(methylenedioxy)phenylhydroxyimino]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- 0.0619^(†) 8.90^(†)(methylenedioxy)phenethyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[2- 0.0795^(†) 3.24^(†)(hydroxymethyl)-4,5-(methylenedioxy)cinnamyl]thio- phene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-{2-[(tetrahydro- 0.0967^(†) 4.144H-pyran-2-ylxoy)methyl]-4,5-(methylenedioxy)cinnamyl}thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4- 0.1006^(†) 4.30^(†)dimethylphenethyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4- 0.180^(†) 2.97^(†)dimethylcinnamyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4- 0.166^(†) 2.97^(†)dimethylcinnamyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(2,4- 0.346^(†) 7.45^(†)dimethylphenoxy)methyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4- 0.308^(†) 4.48^(†)dimethylphenoxy)methyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-5- 28.1^(†) 60.6^(†)(phenylaminocarbonyl)thiophene-2-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[β-acetoxy-2- 0.00544 3.74^(†)methyl-4,5-(methylenedioxy)styryl]thiophene-3-sul- fonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,3,4- 0.000169^(†) 12.5^(†)trimethoxy-6-cyano)phenylaminocarbonyl]thiophene- 3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2- 6.33^(†) 8.82^(†)(cyano)phenyl]benzo[b]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methyl- 0.550^(†) 52.6^(†)enedioxy)phenyl]benzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-tolyl)thio- 0.324^(†) 55.1^(†)phene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-tolyl)thio-0.832^(†) 21.2^(†) phene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-tolyl)thio- 0.302^(†) 31% @100^(†) phene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-0.334^(†) ** methoxyphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(3- 1.32^(†) 56.3^(†)methoxyphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2- 1.71^(†) 59.1^(†)methoxyphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4- 0.184 43.9^(†)ethylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4- 0.0873 8.48^(†)propylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso- 0.218 28.3^(†)propylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4- 0.160 6.11^(†)butylphenyl)thiophene-2-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[2-methyl-4,5- 0.00328^(†) 34.3^(†)(methylenedioxy)phenylacetyl]thiophene-3-sulfona- mideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6- 0.000626^(†) 8.27^(†)trimethylphenylaminocarbonyl)thiophene-3-sulfona- mideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-tri- 0.000238^(†) 3.82^(†)methylphenylacetyl)thiophene-3-sulfonamideN-(4-chloro-5-methyl-3-isoxazolyl)-2-[2-methyl-4,5- 0.000625^(†)3.69^(†) (methylenedioxy)phenylacetyl]thiophene-3-sulfona- mideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- 0.0804^(†) 3.28^(†)(methylenedioxy)cinnamyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4- 0.0555^(†) 3.48^(†)dimethylphenethyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4- 0.000266^(†) 9.78^(†)methoxycarbonyl-2,6-dimethyl)-phenylaminocarbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2- 4.41^(†) 31% @ 100^(†)(phenoxycarbonyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2- 2.71^(†) 20% @ 100^(†)(phenoxycarbonyl)thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-{[3,4- 3.61^(†) 30% @ 100^(†)(methylenedioxy)phenoxy]carbonyl}thiophene-3-sul- fonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2- 0.684^(†) 105^(†)methylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3- 1.20^(†) 111^(†)methylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4- 0.291^(†) 43.2^(†)dimethylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2- 0.761^(†) 29% @ 100^(†)methoxylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3- 0.79^(†) 90^(†)methoxylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4- 1.73^(†) 111^(†)methoxylphenoxy)carbonyl]thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[(4- 5.88^(†) 13% @ 100^(†)methoxylphenoxy)carbonyl]thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[(4- 2.5^(†) 33% @ 100^(†)methoxylphenoxy)carbonyl]thiophene-3-snamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4- 3.2^(†) 43% @ 100^(†)methylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4- 0.648^(†) 68.5^(†)dimethylphenoxy)carbonyl]thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[(2,4- 0.274^(†) 21% @ 100^(†)dimethylphenoxy)carbonyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-{[2-propyl-4,5- 0.138^(†) 11.9^(†)(methylenedioxy)phenoxy]carbonyl}thiophene-3-sul- fonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3- 0.000321^(†) 16.5^(†)methoxycarbonyl-2,4,6-trimethylphenylamino- 0.00092^(†) —carbonyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4- 0.100^(†) 60.3^(†)dimethylphenyl)thiophene-2-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-2.85^(†) 31%^(†) (phenoxycarbonyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso- 0.0823^(†) 2.76^(†)butylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso- 0.155^(†) 3.31^(†)pentylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(2,4,6- 0.0457^(†) 4.68^(†)trimethylphenoxy)methyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4,6- 0.0562^(†) 3.39^(†)trimethylphenoxy)methyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4,6- 0.0490^(†) 1.86^(†)trimethylcinnamyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methyl-4- 0.0468^(†) 3.63^(†)propylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-butyl-2- 0.0468^(†) 1.66^(†)methylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-pentyl-2- 0.107^(†) 2.40^(†)methylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-{[3,4- 0.302^(†) 6.61^(†)(methylenedioxy)phenoxy]methyl}thiophene-3-sul- fonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-{[4,5- 0.107^(†) 0.407^(†)(methylenedioxy)-2-propylphenoxy]methyl}thio- phene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4,6- 0.0417^(†) 1.23^(†)trimethylphenethyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4,6- 0.055^(†) 1.62^(†)trimethylphenethyl)thiophene-2-sulfonamideN-(3,4-dimethyl-5-isoxazolyl-2-[(2,4,6- 0.537^(†) 8% @ 100^(†)trimethylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4,6- 0.0776^(†) 30.2^(†)trimethylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4,6- 0.479^(†) 24.5^(†)trimethylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl- 0.0006^(†) ˜45^(†)2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sul- fonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- 0.0015^(†) ˜>100^(†)carboxymethyl-2,4,6-trimethylphenylamino-carbonyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- 0.0006^(†) >>100^(†)acetoxymethyl-2,4,6-trimethylphenylamino-carbonyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- 0.0004^(†) ˜80^(†)hydroxymethyl-2,4,6-trimethylphenylamino-carbonyl)thiophene-3-sulfonamide *results are generally the average of 2to 5 experiments ≢**preliminary result or results in which one or moredata points were only determined approximately †assay performed withincubation at 24° C.. As described in the Examples, incubation at thehigher temperature reduces the activity by a factor of 2- to about10-compared to the activity at 4° C. —data not available or measured as% inhibition # 100 μM % % inhibition # 100 μM

It is understood that 4-bromo or 4-chloro groups can be replaced byother 4-halo substituents or other suitable substituents for R¹, such asalkyl, particularly alkyl with between about 1 and 15 carbons in thechain.

2. Ar² is a substituted 4-biphenyl group

Compounds of formulae I in which Ar¹ is N-(5-isoxazolyl) orN-(3-isoxazolyl) in which Ar² is selected from biphenyl derivatives areprovided. These compounds can be represented by the following formulae(VII):

in which R²⁶ and R¹³ are each independently selected from H, OH, HONH,NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, alkoxy, alkylamino, dialkylamino, alkylthio,haloalkoxy, haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino,arylthio, arylsulfinyl, arylsulfonyl, haloalkyl, haloaryl,alkoxycarbonyl, carbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl,formyl, substituted or unsubstituted amido, substituted or unsubstitutedureido, in which the alkyl, alkenyl and alkynyl portions contain from 1up to about 14 carbon atoms, preferably from 1 to 6 atoms, and areeither straight or branched chains or cyclic, and the aryl portionscontain from about 4 to about 16 carbons, preferably 4 to 10 carbons.R¹³ and R²⁶ are preferably each selected from H, loweralkyl, haloalkyland halide. Again, it is understood that Ar² may be substituted withmore than one substituent, each of which is selected independently fromthe selections set forth for R²⁶ and R¹³, and R² and R¹ are as definedabove.

In the embodiments herein, the biphenylsulfonamides are substituted4-biphenylsulfonamides, R¹³ is preferably at the para position and R²⁶,if it is not hydrogen, is at any position except the 2-position.

In more preferred embodiments, R¹ is halide or methyl or higher (C₉-C₁₃)alkyl. R¹ is selected from halide, CH₃, C₂H₅, CF₃, C₂F₅, n—C₃H₇ andcyclo-C₃H₇, preferably halide or CH₃, and R² is selected from H, CH₃,C₂H₅, CF₃, C₂F₅, n-C₃H₇ and cyclo—C₃H₇, more preferably R¹ is halide orCH₃, and R² are selected from H, CH₃, C₂H₅, or CF₃.

In more preferred embodiments, R¹ is Cl or Br, or if greater ET_(B)activity is preferred a higher alkyl (C₉H₁₉ to C₁₃H₂₇; R² is selectedfrom H, CH₃, C₂H₅, CF₃, C₂F₅, n—C₃H₇, cyclo—C₃H₇, nC₁₃H₂₇ and nC₉H₁₉ Inyet more preferred embodiments, R¹ is Br, Cl or C₉H₁₉ to C₁₃H₂₇; R² isH, CH₃, C₂H₅, or CF₃.

The biphenyl compounds provided herein are generally ET_(B) active orET_(B) selective (see, e.g., Table 2); i.e. the compounds providedherein inhibit binding of endothelin to ET_(B) receptors atconcentrations about 10- to about 30-fold less than they inhibit bindingof endothelin to ET_(A) receptors. In particular the4-biphenylsulfonamides are ET_(B) selective.

In general in all embodiments herein, 4-haloisoxazolyl sulfonamidesexhibit substantially enhanced activity with respect to at least one ofthe ET receptors (about two-fold to twenty-fold greater activity), asassessed by assays, such as those provided herein, that measure bindingto ET_(A) and/or ET_(B) receptors, compared to correspondingsulfonamides in which the substituent at the 4 position in theisoxazolyl is other than halo, such as alkyl. For example: the IC₅₀ ofN-(3,4-dimethyl-5-isoxazolyl)-2-biphenylsulfonamide for ET_(A) receptorsis about 0.008 μM, whereas, the IC₅₀ ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfonamide is about 0.0016μM (see, Table 2 below); and (3) the IC₅₀ ofN-(3,4-dimethyl-5-isoxazolyl)-3-biphenylsulfonamide for ET_(B) receptorsis about 3.48 μM; whereas, the IC₅₀ ofN-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide for ET_(B)receptors is about 0.76 μM and the IC₅₀ ofN-(4-chloro-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide for ET_(B)receptors is about 0.793 μM (see, Table 2 below).

Exemplary biphenyl sulfonamides are the following and those set forth inTable 2, and include, but are not limited to:N-(3-methyl-5-isoxazolyl)-4′-methylphenyl-4-biphenylsulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-4′-methylphenyl-4-biphenylsulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-4′-methylphenyl-4-biphenylsulfonamide,(3-methyl-5-isoxazolyl)-4′-trifluorophenyl-4-biphenylsulfonamide,(4-bromo-3-methyl-5-isoxazolyl)-4′-trifluorophenyl-4-biphenylsulfonamide,(3-methyl-5-isoxazolyl)-4′-methyoxyphenyl-4-biphenylsulfonamide,(4-bromo-3-methyl-5-isoxazolyl)-4′-methoxyphenyl-4-biphenylsulfonamide,(4-bromo-3-methyl-5-isoxazolyl)-3′-methoxyphenyl-4-biphenylsulfonamide,(4-bromo-3-methyl-5-isoxazolyl)-2′-methoxyphenyl-4-biphenylsulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3′,4′-methylenedioxyphenyl-4-biphenylsulfonamide and(4-bromo-3-methyl-5-isoxazolyl)-3′-methylphenyl-4-biphenylsulfonamide.Corresponding 4-chloro and 4-fluoro isoxazolyl compounds are alsoencompassed herein.

Exemplary biphenyl compounds were tested using the exemplified assays(see, EXAMPLES) and the results, which are intended to be exemplary orprovided for comparison with compounds provided herein, and are notlimiting, are as set forth in the following table (Table 2):

TABLE 2 COMPOUND ET_(A) (μM)* ET_(B) (μM)*N-(4-bromo-3-methyl-5-isoxazolyl)-4-biphenylsulfo- 3.3 ˜0.17 namide49^(†) 1.23^(†) N-(4-bromo-5-methyl-3-isoxazolyl)-4-biphenylsulfo- 6.4 ±2 0.29 ± 0.02 namide 49^(†) 1.78^(†)N-(4-chloro-3-methyl-5-isoxazolyl)-4-biphenylsulfo- 4.93 ± 3 0.29 ± 0.1namide N-(3,4-dimethyl-5-isoxazolyl)-4-biphenylsufonamide 9.9 ± 1.4 0.77± 0.32 6.3^(†) 0.15^(†)N-(4-chloro-5-methyl-3-isoxazolyl)-4-biphenylsulfo- 3.7 0.23 ± 0.01namide 18.6^(†) 1.29^(†) N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-4-19.0 1.7 biphenylsulfonamide — 5.62^(†)N-(4-Tridecyl-3-trifluoromethyl-5-isoxazolyl)-4- 34.0 ± 9 0.99 ± 0.2biphenylsulfonamide 33.0^(†) 0.95^(†)N-(3,4-dimethyl-5-isoxazolyl)-2-biphenylsulfona- 0.0083 ± 0.0014 12.8mide N-(4-bromo-3-methyl-5-isoxazolyl)-2-biphenylsulfo- 0.00127** 8.54**namide N-(4-chloro-3-methyl-5-isoxazolyl)-2-biphenylsulfon- 0.00123**˜14** amide N-(3,4-dimethyl-5-isoxazolyl)-3-biphenylsulfona- >0.03**3.48** mide N-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylsulfo- ˜0.03**0.76** namideN-(4-chloro-3-methyl-5-isoxazolyl)-3-biphenylsulfo- >0.03** 0.793**namide N-(4-bromo-3-methyl-5-isoxazolyl)-4′- 14.53 ± 9.6 0.046 ± 0.044methylphenyl-4-biphenylsulfonamide 22.17 ± 3.77^(†) 0.168 ± 0.0032^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-4′- 5.4 ± 0.3 0.083 ± 0.02trifluorophenyl-4-biphenylsulfonamide 25.9 ± 13.7^(†) 0.71 ± 0.43^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-4′- 14.7 ± 5.6 1.15 ± 0.44methoxyphenyl-4-biphenylsulfonamide 121.5 ± 2.12^(†) 3.94.± 0.89^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-3′- 4.97 ± 3.4 0.66 ± 0.25methoxyphenyl-4-biphenylsulfonamide 162.6 ± 7.14^(†) 2.08 ± 0.23^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-2′- 3.3 ± 3.5 0.41 ± 0.14methoxyphenyl-4-biphenylsulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3′,4′- 38.2 ± 4.95^(†) 3.0 ± 0.78^(†)methylenedioxyphenyl-4-biphenylsulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3′- — —methylphenyl-4-biphenylsulfonamide *results generally from 1, 2 or 3experiments with the same preparation **preliminary results

Preferred compounds are those in which Ar² is a 4-biphenyl in which,referring to formula Vll and at least one substituent R¹³ is at the paraposition. Preferred substituents are loweralkyl, halo loweralkyl andlower alkoxy. Such compounds are ET_(B) active.

The preparation of the above and other compounds that possess therequisite activities are set forth in the Examples.

B. Sulfonamides and Sulfonamide Derivatives

Sulfonamides and sulfonamide derivatives are also provided. Thesecompounds are active in assays which measure endothelin antagonistactivity. The sulfonamides are of formula:

where Ar¹ is isoxazolyl and Ar² has the formula:

where R³ and R⁴ are hydrogen, or are substituents which are believed toprovide enhanced tolerability of the compounds (i.e., by altering thepharmacokinetic profile of the compound). Such substituents arepreferably independently selected from halo, cyano, cyanoalkyl, C(O)R⁴¹,alkyl, alkenyl, cycloalkyl and aryl, or R³ and R⁴ together formalkylene; W is O, NH or CH₂;

R⁵, R⁶ and R⁷ are each independently selected as in (i) or (ii):

(i) R⁶ is hydrogen, unsubstituted alkyl, hydroxy, unsubstituted alkoxy,C(O)R⁴¹, carbamoyloxy or alkoxycarbonyloxy, and

R⁵ and R⁷ are each independently selected from hydrogen, unsubstitutedalkyl, hydroxy, C(O)R⁴″, carbamoyloxy and alkoxycarbonyloxy; or

(ii) if at least one of R³ and R⁴ is not hydrogen, then any two may formalkylenedioxy, and the other is selected as in (i); and

R⁴⁵ is selected from among alkyl, C(O)R⁴¹, (CH₂)_(x)OH andCH(OH)(CH₂)_(x)CH₃ in which x is 0-6, S(O)_(n)R⁴¹ in which n is 0-2 andC(═NR⁴³)R⁴¹; R⁴¹ is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino,(aryl)(alkyl)amino, alkylsulfonylamino, arylsulfonylamino,(alkylsulfonyl)(alkyl or aryl)amino or (arylsulfonyl)(alkyl oraryl)amino; and R⁴³ is selected from hydroxy, alkoxy, alkyl and aryl.R⁴¹ and R⁴³ are unsubstituted or substituted with one or moresubstituents selected from Y, which is defined as alkoxy, halide,pseudohalide, alkylcarbonyl, arylcarbonyl, amino, alkylamino,dialkylamino, carboxyl, alkoxycarbonyl, aryloxycarbonyl or hydroxy. Alsoof interest are the corresponding 3-acyl-2-thiophenesulfonamides.

These compounds appear to exhibit superior potency, efficacy,bioavailability, in vivo half-life and/or stability compared withcompounds where the aryl group has more than two hydrogen substituents,while avoiding toxicological effects associated with hydrophobicity(see, Table 4). In addition, these compounds appear to exhibit goodprofiles in standard in vitro toxicity tests.

It has been found that for in vivo administration, it is desirable toachieve the proper degree of hydrophilicity, which reduces potentialhemolytic properties of the compounds. It has been found herein, forexample, that this is achieved if the aryl group is tetra-, penta- orhexasubstituted, preferably pentasubstituted. If the aryl group istetrasubstituted, it will preferably be substituted at the 2, 4 and 6positions, and one of these substituents will be a polar group, such ashydroxyl, acetoxy, carboxyl and carboxamide. Such substitution enhancesthe endothelin antagonist activity and the hydrophilicity of thecompounds. If the aryl group is substituted at the 2, 4 and 6 positionswith nonpolar groups, such as alkyl groups, more specifically methylgroups, then the aryl group will preferably be penta- orhexasubstituted. In pentasubstituted aryl groups, the fifth substituentwill be at the 3 position and will preferably be a polar group, such ashydroxyl, acetoxy, carboxyl and carboxamide. Such substitution ispreferred to achieve highest levels of activity for therapeutic use.

Such substitution provides compounds with good bioavailability, long invivo half-life, and/or good in vivo efficacy. In view of the disclosureherein, other such optimal substituent patterns and substituents can bedetermined empirically using suitable animal models.

As noted above, the compounds of this embodiment provide enhancedtolerability as compared to similar compounds known in the art. Suchenhanced tolerability is manifested through alteration of thepharmacokinetic profile of the compounds. The pharmacokinetic profile isbased on a number of factors, including, but not limited to,bioavailability, in vivo half-life, in vivo efficacy, potency,stability, receptor-selectivity, and the like.

In certain embodiments, the compounds are selected with the proviso thatat most one of R⁵, R⁶ and R⁷ is hydrogen and that the compound is notN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethylphenylaminocarbonyl)-thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamide,N-(3,4-dimethyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)carbonyl]thiophene-3-sulfonamideorN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)-carbonyl]thiophene-3-sulfonamide.

In other embodiments, the sulfonamides are selected with the furtherproviso that the compound is notN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocarbonyl)-thiophene-3-sulfonamide,N-(4-chloro-5-methyl-3-isoxazolyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamideorN-(3,4-dimethyl-5-isoxazolyl)-2-(3-hydroxy-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide.

Preferred compounds include those in which R³ and R⁴ are eachindependently hydrogen, alkyl, halo, cyano, cyanomethyl, acetyl orcycloalkyl, or together form alkylene;

R⁵, R⁶ and R⁷ are each independently selected as in (i) or (ii), withthe proviso that at most one of R⁵, R⁶ and R⁷ are hydrogen:

(i) R⁶ is hydrogen, unsubstituted alkyl, hydroxy, unsubstituted alkoxy,C(O)R⁴¹, carbamoyloxy or alkoxycarbonyloxy, and

R⁵ and R⁷ are each independently selected from hydrogen, unsubstitutedalkyl, hydroxy, C(O)R⁴¹, carbamoyloxy or alkoxycarbonyloxy; or

(ii) if at least one of R³ and R⁴ is not hydrogen, then any two may formmethylenedioxy, and the other is selected as in (i);

x is 0 or 1; n is 2; R⁴¹ is alkyl, cycloalkyl, alkylamino, dialkylamino,arylamino, diarylamino, alkylsulfonylamino or arylsulfonylamino; and R⁴³is hydroxy or alkoxy, with the proviso that the compound is notN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethylphenylaminocarbonyl)-thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamide,N-(3,4-dimethyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)carbonyl]thiophene-3-sulfonamideorN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)-carbonyl]thiophene-3-sulfonamide.

In particular, compounds which are preferred are those in which Ar¹ is4-chloro-3-methyl-5-isoxazolyl; R³ and R⁴ are each independentlyhydrogen, methyl, cyclopropyl, fluoro, chloro, cyano, cyanomethyl oracetyl, or together form butylene;

R⁵, R⁶ and R⁷ are each independently selected from (i) or (ii), with theproviso that at most one of R⁵, R⁶ and R⁷ is hydrogen:

(i) R⁶ is selected from hydrogen, methyl, hydroxy, methoxy, acetyl,carbamoyloxy and methoxycarbonyloxy, and

R⁵ and R⁷ are each independently hydrogen, methyl, hydroxy, acetyl,carbamoyloxy and methoxycarbonyloxy; or

(ii) if at least one of R³ and R⁴ is not hydrogen, then R⁶ and R⁷ mayform methylenedioxy and R⁵ is selected as in (i); and

R⁴⁵ is acetyl, propanoyl, 2-methylpropanoyl, cyclopropylcarbonyl,benzoyl, cyclohexylcarbonyl, methyl, 1-hydroxy-1-ethyl, hydroxymethyl,methoxyacetyl, fluoroacetyl, carboxyacetyl, hydroxyacetyl, oximinoacetylor SO₂R⁴, with the proviso that the compound is notN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethylphenylaminocarbonyl)-thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamide,N-(3,4-dimethyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)carbonyl]thiophene-3-sulfonamideorN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)-carbonyl]thiophene-3-sulfonamide.

Particularly preferred compounds are selected from the following:

N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide,

N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazoiyi)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-2-thiophenecarboxamide,

3-1((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,

3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-2,4,6-trimethylphenylcarbamate,

3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-2,4,6-trimethylphenylmethyl carbonate,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1-methylethyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxyethyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4-methylphenyl)-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,

3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-3,5-dimethylphenyl)-3-oxopropanoicacid,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6-dimethylphenyl)-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-methylsulfonyl)phenyl)-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((methylamino)sulfonyl)phenyl)-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((dimethylamino)sulfonyl)phenyl)-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-(((methylsulfonyl)amino)carbonyl)phenyl)-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,

N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide,

N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,

3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(5-methylthienyl))carbonyl)amino)-2,4,6-trimethylphenylcarbamate,

3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(5-methylthienyl))carbonyl)amino)-2,4,6-trimethylphenylmethyl carbonate,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-5-methyl-3-thiophenesulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)-5-methyl-3-thiophenesulfonamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1-methylethyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxyethyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4-methylphenyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,

3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(5-methylthienyl))carbonyl)amino)-3,5-dimethylphenyl)-3-oxopropanoicacid,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-methylsulfonyl)phenyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((methylamino)sulfonyl)phenyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((dimethylamino)sulfonyl)phenyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-(((methylsulfonyl)amino)carbonyl)phenyl)-5-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,

N-(6-acetyl-4-methyl-1,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide,

N-(4-acetyl-6-methyl-1,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide,

N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide,

5N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino_)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,

3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4-methylthienyl))carbonyl)amino)-2,4,6-trimethylphenylcarbamate,

3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4-methylthienyl))carbonyl)amino)-2,4,6-trimethylphenylmethyl carbonate,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-4-methyl-3-thiophenesulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)-4-methyl-3-thiophenesulfonamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1-methylethyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxyethyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4-methylphenyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,

3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4-methylthienyl))carbonyl)amino)-3,5-dimethylphenyl)-3-oxopropanoicacid,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazoiyl)amino)sulfonyl)-N-(2,4-dimethyl-6-methylsulfonyl)phenyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((methylamino)sulfonyl)phenyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((dimethylamino)sulfonyl)phenyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-(((methylsulfonyl)amino)carbonyl)phenyl)-4-methyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,

N-(6-acetyl-4-methyl-1,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide,

N-(4-acetyl-6-methyl-1,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide,

N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide,

N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4,5-dimethylthienyl))carbonyl)amino)-2,4,6-trimethylphenylcarbamate,

3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4,5-dimethylthienyl))carbonyl)amino)-2,4,6-trimethylphenylmethyl carbonate,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-4,5-dimethyl-3-thiophenesulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)-4,5-dimethyl-3-thiophenesulfonamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1-methylethyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxyethyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4-methylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4,5-dimethylthienyl))carbonyl)amino)-3,5-dimethylphenyl)-3-oxopropanoicacid,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-methylsulfonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((methylamino)sulfonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((dimethylamino)sulfonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-(((methylsulfonyl)amino)carbonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide,

3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,

N-(6-acetyl-4-methyl-1,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide,and

N-(4-acetyl-6-methyl-1,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide.

Also among the preferred compounds are those selected from thefollowing:

N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-cyclopropyl-2-thiophenecarboxamide,

5-acetyl-(N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide,

N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-cyano-2-thiophenecarboxamide,

N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-(cyanomethyl)-2-thiophenecarboxamide,

N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-fluoro-2-thiophenecarboxamide,

N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-chloro-2-thiophenecarboxamide,and

N-2-acetyl-4,6-dimethylphenyl)-5-chloro-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide.

Preferred compounds are also those where W is O or CH₂. The sulfonamidesare thus 2-phenoxycarbonyl-3-sulfonamide,3-phenoxycarbonyl-2-sulfonamide, 2-phenylacetyl-3-sulfonamide and3-phenylacetyl-2-sulfonamide derivatives of the above compounds.

Table 3 sets forth exemplary compounds of this embodiment anddemonstrates that the compounds have activity as endothelin receptorantagonists. More preferred compounds of Table 3 are those that have thehighest activities, and preferred substituents are those on thecompounds with the highest activities. The data in Table 3 is intendedfor exemplary and comparison purposes only and is not intended to limitthe scope of this embodiment in any way.

TABLE 3 COMPOUND ET_(A) (μM)* ET_(A)/ET_(B)N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3- 0.00055^(†) 34000^(∥)methyl-5-isoxazolyl)amino)sulfonyl)-2- thiophenecarboxamide3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N- 0.00111^(†)14000^(∥) (2-isobutyryl-4,6-dimethylphenyl)-2- thiophenecarboxamideN-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3- 0.00426^(†)  6000^(∥)methyl-5-isoxazolyl)amino)sulfonyl)-2- thiophenecarboxamideN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3- 0.00294^(†)  9000^(∥)methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2- thiophenecarboxamide3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N- 0.00061^(†)21000^(∥) (2,4-dimethyl-6-propionylphenyl)-2- thiophenecarboxamide3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N- 0.00036^(†)45000^(∥) (2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N- 0.0149^(†) 1300^(∥) (2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide 3-(((3-(((4-chloro-3-methyl-5- 0.00075^(†) —isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-2,4,6-trimethylphenyl methyl carbonate 3-(((3-(((4-chloro-3-methyl-5-0.00545^(†) — isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-2,4,6-trimethyiphenyl carbamate *results are generally the average of 2to 5 experiments ^(†)assay performed with incubation at 24° C. Asdescribed in the Examples, incubation at the higher temperature reducesthe activity by a factor of 2- to about 10- compared to the activity at4° C. — data not available or measured as % inhibition @ 100 μM^(∥)ET_(A)/ET_(B) selectivity

Table 4 lists oral half-life, bioavailability, and in vivo activity ofselected exemplary compounds. The in vivo activity was measured in apulmonary hypertension model and is a measure of the activity of thecompounds at selected dosages. As Table 4 indicates, the compoundsclaimed herein exhibit improved oral half-life, bioavailability, and/orin vivo activity over those disclosed previously (see, e.g., PCTInternational Publication No. WO 96/31492).

TABLE 4 POt_(½) Peak in Plasma in vivo COMPOUND P_(app) ^(a) Rat^(b)Levels^(c) Efficacy^(d) N-(4-chloro-3-methyl-5-isoxazolyl)-2- 2.32 4.1173 ++ [2-methyl-4,5-(methylenedioxy)phenyl-acetyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-0.58 [(2,3,4-trimethoxy-6-cyano)phenyl-aminocarbonyl]thiophene-3-sulfona- mideN-(4-chloro-3-methyl-5-isoxazoly)-2- 1.78 3.4 40.2 ++(3-cyanomethyl-2,4,6-trimethylphenyl- aminocarbonyl)thiophene-3-sulfona-mide N-(4-chloro-3-methyl-5-isoxazolyl)-2- 1.10(3-carboxymethyl-2,4,6-trimethyl- phenylaminocarbonyl)thiophene-3-sul-fonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2- 1.56 1.5 3 −/+(3-hydroxymethyl-2,4,6-trimethyl- phenylaminocarbonyl)thiophene-3-sul-fonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2- 5.9 2.6(3-methanesulfonylamino-2,4,6- trimethylphenylaminocarbonyl)thio-phene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2- 3.9 20 ++(3-cyano-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulfonamideN-(2-acetyl-4,6-dimethylphenyl)-3-(((4- 40% 8.6 57 ++^(e)chloro-3-methyl-5- isoxazolyl)amino)sulfonyl)-2- thiophenecarboxamide3-(((4-chloro-3-methyl-5- 5.4 59 isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-2- thiophenecarboxamide3-(((4-chloro-3-methyl-5- 5.5 53 isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6- dimethylphenyl)-2- thiophenecarboxamide ^(a)×10⁻⁶ cm/sec ^(b)in hours ^(c)in μg/mL ^(d)Pulmonary Hypertension model:++ effective at 5 mg/kg − no effect at 5 mg/kg + effective at 15 mg/kg^(e)effective at 0.3 mg/kg in vivo

C. Preparation of the Compounds

The preparation of the neutral (i.e., free) sulfonamide compounds thatpossess the requisite activities are set forth in U.S. Pat. Nos.5,464,853, 5,594,021, 5,591,761, 5,571,821, 5,514,691, 5,464,853,commonly owned co-pending U.S. application Ser. Nos. 08/721,183 and08/847,797, and commonly owned published International POT applicationNos. WO 96/31492 and WO 94/27979. Representative syntheses are set forththe Examples. Compounds whose synthesis is not explicitly exemplifiedherein or in the above-listed patents and published International POTapplications, can be synthesized by routine modification of one or moremethods described in detail in the Examples by substituting appropriatereadily available reagents.

Salts, acids and other derivatives thereof can be synthesized asoutlined and exemplified herein, or by other methods known to those ofskill in the art.

1. Neutral Compounds

In general, most of the syntheses involve the condensation of a sulfonylchloride with an aminoisoxazole in dry pyridine or in tetrahydrofuran(THF) and sodium hydride. The sulfonyl chlorides and aminoisoxazoleseither can be obtained commercially or synthesized according to methodsdescribed in the Examples or using other methods available to those ofskill in this art (see, e.g., U.S. Pat. Nos. 4,659,369, 4,861,366 and4,753,672).

The N-(alkylisoxazolyl)sulfonamides can be prepared by condensing anaminoisoxazole with a sulfonyl chloride in dry pyridine with or withoutthe catalyst 4-(dimethylamino)pyridine. TheN-(3,4-dimethyl-5-isoxazolyl)sulfonamides andN-(4,5-dimethyl-3-isoxazolyl)sulfonamides can be prepared from thecorresponding aminodimethylisoxazole, such as5-amino-3,4-dimethylisoxazole. For example,N-(3,4-dimethyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamidewas prepared from 2-methoxycarbonylthiophene-3-sulfonyl chloride and5-amino-3,4-dimethylisoxazole in dry pyridine.

The N-(4-haloisoxazolyl)sulfonamides can be prepared by condensation ofamino-4-haloisoxazole with a sulfonyl chloride in THF with sodiumhydride as a base. For example,N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide was preparedfrom 5-amino-4-bromo-3-methylisoxazole and thiophene-2-sulfonyl chloridein THF and sodium hydride.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-isoxazolyl)thiophene-2-sulfonamidewas prepared from 5-amino-4-bromo-3-methylisoxazole and5-(3-isoxazolyl)thiophene-2-sulfonyl chloride.

Alternatively, compounds, such as those in which Ar² is thienyl, furyland pyrrolyl herein, may be prepared by reacting an appropriate sulfonylchloride with a 5-aminoisoxazole substituted at the 3 and 4 positions,such as 5-amino-4-bromo-3-methylisoxazole, in tetrahydrofuran (THF)solution containing a base, such as sodium hydride. Following thereaction, the THF is removed under reduced pressure, the residuedissolved in water, acidified and extracted with methylene chloride. Theorganic layer is washed and then dried over anhydrous magnesium sulfate,the solvents are evaporated and the residue is purified byrecrystallization using hexanes/ethyl acetate to yield pure product.

These sulfonamides also can be prepared from the corresponding sulfonylchloride and the aminoisoxazole in pyridine with or without a catalyticamount of 4-dimethylaminopyridine (DMAP). In some cases, thebis-sulfonyl compound is obtained as the major or exclusive product. Thebis-sulfonated products can be readily hydrolyzed to the sulfonamideusing aqueous sodium hydroxide and a suitable co-solvent, such asmethanol or tetrahydrofuran, generally at room temperature.

Other examples include:

(a)N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamidewas prepared fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide,aniline and 1-ethyl-3′-[3-dimethylaminopropyl]carbodiimide (EDCI).N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamidewas prepared from 4-methoxyaniline, N,N′-diisopropylethylamine andN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide.N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzylaminocarbonyl)thiophene-3-sulfonamidewas prepared fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide andbenzylamine as described above.

N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide wasprepared fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide,which was prepared from the condensation of5-amino-4-bromo-3-methylisoxazole and2-(carbomethoxy)thiophene-3-sulfonyl chloride.

(b)N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4′-isopropylphenyl)pyrrole-2-sulfonamideandN-(4-bromo-3-methyl-5-isoxazolyl)-1-(4′-isopropylphenyl)pyrrole-3-sulfonamidewere prepared from 5-amino-4-bromo-3-methylisoxazole and a mixture of1-(4′-isopropylphenyl)pyrrole-2-sulfonyl chloride and1-(4′-isopropylphenyl)pyrrole-3-sulfonyl chloride. These sulfonylchlorides were prepared from 1-(4′-isopropylphenyl)pyrrole-2-sulfonicacid, phosphorus oxychloride and phosphorus pentachloride.1-(4′-isopropylphenyl)-pyrrole-2-sulfonic acid was prepared from1-(4′-isopropylphenyl)pyrrole and chlorosulfonic acid.1-(4′-isopropylphenyl)pyrrole was prepared from 4-isopropylaniline and2,5-dimethoxytetrahydrofuran.

2. Salts of the Neutral Compounds

Pharmaceutically-acceptable salts of the compounds may be prepared bythe exemplified method or any other method known to those of skill inthe art. As exemplified herein, in the case of organic salts, theorganic base, such as N,N′-dibenzylethylenediamine, chloroprocaine,choline, ammonia, diethanolamine and other hydroxyalkylamines,ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine, or tris(hydroxymethyl)aminomethane,may be mixed with an equimolar amount of the sulfonamide. Subsequentrecovery of the salt by crystallization, precipitation, concentration ofthe solution, lyophilization, spray-drying, chromatography, including,but not limited to, normal- and reverse-phase chromatography or resinchromatography, or any other method known to those of skill in the artwould provide the desired salts. The pharmaceutically acceptablecationic salts can be prepared by reacting the acid forms with anappropriate base.

3. Salts of Hydrophobic Sulfonamides

A process of making an alkali metal salt of hydrophobic sulfonamidemodulators of endothelin activity is provided. More particularly,processes for making sodium salts of such sulfonamides are provided.Each process includes the steps of dissolving the free sulfonamide in anorganic solvent in the presence of a saturated aqueous solution of analkali metal salt and recovering and purifying the sulfonamide salt.

The sulfonamide to be converted to an alkali metal salt can be made byany process well known in the art (see, eg., U.S. Pat. Nos. 5,591,761and 5,594,021). By way of example,N²-methoxy-N²-methyl-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamideis reacted with 6-methylbenzo[d][1,3]dioxolyl-5-methyl magnesiumchloride in an organic solvent to provide4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazoleas a crude product that is purified be preparative HPLC.

A Process for Preparation of Alkali Metal Salts

An alternative process for preparing the salts is provided herein andexemplified below (see, Example 7). Briefly, the process includes thesteps of (a) admixing 5-chloromethyl-6-methylbenzo[d][1,3]dioxole andactivated magnesium in tetrahydrofuran to form a Grignard reagent; (b)addingN²-methoxy-N²-methyl-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamideto the reaction admixture; (c) diluting the mixture from step (b)sequentially with a concentrated inorganic acid and an organic solventto form an aqueous layer and an organic layer; and (d) drying theorganic layer and evaporating the solvent to form a residue.

The salt-forming process of begins with dissolution of the freesulfonamide in an organic solvent. Suitable organic solvents suitablefor use in these processes are well known in the art. Exemplary andpreferred organic solvents are ethyl acetate, methyl t-butyl ether,methylene chloride, THF, ether, acetonitrile, dioxane and chloroform.Ethyl acetate is the most preferred organic solvent.

Formation of the alkali metal salt proceeds by exposing the organicsolvent containing the free sulfonamide to a saturated solution of analkali metal salt. The particular salt used with depend on the desiredsulfonamide salt to be formed. Alkali metals suitable for use in thepresent process are well known in the art and include sodium, potassium,calcium, magnesium and the like. For preparation of a sulfonamide saltuseful for a pharmaceutical composition, sodium and calcium are thepreferred alkali metals. Sodium is most preferred. Anionic components ofthe salt are well known in the art and include carbonate, phosphate,bicarbonate, nitrate, hydroxide and the like and combinations thereof.Carbonate, bicarbonate and hydroxide anions are preferred. Bicarbonateis more preferred. The alkali metal salt used to form the sulfonamidesalt is in the form of a highly concentrated aqueous solution. It ispreferred that saturated solutions be used. Means for making saturatedalkali metal salt solutions are well known in the art. The biphasicmixture is agitated by any number of methods including shaking,stirring, sonication, etc. After allowing the layers to separate, theaqueous phase is removed.

Recovery of the product from the organic solvent is accomplished usingany means well known in the art, such as crystallization and filtration.In one embodiment, the organic solvent containing the sulfonamide saltis washed with a concentrated salt solution, wherein the alkali metal isthe same as used for salt formation. Where the alkali metal salt issodium, exemplary wash solutions are concentrated solutions of sodiumchloride (e.g, brine) or sodium bicarbonate. Once the protonated form ofthe sulfonamide has been converted to the salt form, it is important touse concentrated (> than about 3 percent by weight) salt wash solutions.Surprisingly, the alkali metal sulfonamide salt is more soluble inorganic solvents than in saturated alkali metal solutions. Use of adiluted solution of salt (e.q., half-strength brine) or water forwashing the organic solvent may cause disproportionation of the productbetween water and the organic layer, and subsequent loss of material.After washing, the product solution can be dried concentrated to providecrude product as, for example, a residue. In a preferred embodiment,drying occurs over Na₂SO₄ or MgSO₄ and concentration occurs in vacuo.

The residue is further recovered and purified using recrystallization.In accordance with this embodiment, the product is dissolved in aorganic, non-water miscible solvent. Such solvents are well known in theart. Exemplary and preferred such solvents are ether and halomethanessuch as dichloromethane and chloroform. A combination of such solventscan also be used. The crystalline product can be isolated from theorganic solvent via filtration. The recovered product can be washed oneor more times with the organic, non-water miscible solvent. A detaileddescription of the making of4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole,sodium salt in accordance with the disclosed process can be foundhereinafter in the Examples.

The sulfonamide salts provided herein can be converted back to the freesulfonamide form and further purified by this process. The sulfonamidesalt is dissolved in an aqueous solvent (e.g., water) and filtered.Preferably, filtration occurs through more than one layer of filterpaper. Negative pressure or suction may not be needed to completefiltration. In some cases, the large amount of impurities that are notsoluble in water (10% or higher) slows down the filtration process. Thisproblem can be avoided by using a larger size of filter during thefiltration. Usually there is no problem with filtration if the purity ofthe crude salt is 90% or higher.

The isolation salt, typically in the form of a turbid solution, isconverted to an acid by exposing the salt to a concentrated inorganicacid. Suitable acids include hydrochloric acid (HCl), sulfuric acid(H₂SO₄), nitric acid (H₂NO₃) and the like. Acidification continues untilthe pH of the product solution is about 1.5 to about 2.5. Acidificationpreferably takes place at temperatures below about 10° C. The productcan precipitate as a milky, non-filtrable material during acidification.The slow, dropwise addition of some extra amount of acid causes theproduct to form a fine, easy filterable precipitate. The precipitate isfiltered off, washed with water until neutral and pressed on the filterto get rid of excess water. The obtained free acid is typically >95%pure as determined by HPLC. The purified sulfonamide can then beconverted to the alkali metal salt by the previously describedprocedure.

Practicing the process provided herein permits shortened reaction times,and results in a more pure product than is possible with other methods.Direct isolation of the sulfonamide salt may be achieved by mixing theproduct with concentrated alkali salt solutions and organic solvents. Asurprising key observation is that the sulfonamide salt stays in theorganic layer, so long as the aqueous layer is heavily salted ratherthan the aqueous layer as expected. This permits direct isolation of thesalt, which can be further purified by conversion to the freesulfonamide and back to the salt, as well as recrystallization. Thisdiscovery is key to synthesizing sulfonamide salts with high purity atlarge scale.

4. Other Derivatives

Prodrugs and other derivatives of the compounds suitable foradministration to humans may also be designed and prepared by methodsknown to those of skill in the art (see, eg., Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392).

Compounds described herein have been synthesized and tested for activityin in vitro assays and, in some cases, in in vivo animal models. Nuclearmagnetic resonance spectroscopic (NMR), mass spectrometric, infraredspectroscopic and high performance liquid chromatographic analysesindicated that the synthesized compounds have structures consistent withthose expected for such compounds and are generally at least about 98%pure. All of the compounds exemplified or described herein exhibitedactivity as endothelin antagonists.

D. Formulation of Sulfonamides and Sulfonamide Salts

Formulations of the sulfonamides and sulfonamide salts described aboveare provided herein. The formulations prepared as described below arecompositions designed for administration of the pharmaceuticallyacceptable derivatives, particularly salts of the sulfonamide compoundsprovided herein. Because of the observed superior stabilitycharacteristics of the salts, compared to the neutral forms, such salts,particularly the sodium salts are particularly suitable for oral andparenteral administration. Such compositions include solutions,suspensions, tablets, dispersible tablets, pills, capsules, powders, drypowders for inhalers, sustained release formulations and any othersuitable formulation. Preferably the compositions will take the form ofa pill or tablet. Methods for manufacture of tablets, capsules and othersuch formulations are known to those of skill in the art (see, e.g.Ansel, H. C (1985) Introduction to Pharmaceutical Dosage Forms, 4thEdition, pp. 126-163).

It is understood that for the formulations herein, derivatives,including pharmaceutically acceptable acids, esters, salts and prodrugsof these compounds are preferred. Preferred for use herein for preparingthe formulations are sodium salts, particularly the sodium salt in whichNa⁺ is the counter ion.

In the formulations, effective concentrations of one or morepharmaceutically acceptable derivatives is (are) mixed with a suitablepharmaceutical carrier or vehicle. Preferably, the sulfonamide compoundsare derivatized as the corresponding salts, preferably sodium salts,prior to formulation, as described above. The concentrations of thesalts of the compounds in the formulations are effective for delivery ofan amount, upon administration, that ameliorates the symptoms of theendothelin-mediated disease. Typically, the compositions are formulatedfor single dosage administration. To formulate a composition, the weightfraction of compound is dissolved, suspended, dispersed or otherwisemixed in a selected vehicle at an effective concentration such that thetreated condition is relieved or ameliorated.

Pharmaceutical carriers or vehicles suitable for administration of thecompounds provided herein include any such carriers known to thoseskilled in the art to be suitable for the particular mode ofadministration. In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients. Liposomal suspensions, includingtissue-targeted liposomes, may also be suitable as pharmaceuticallyacceptable carriers. These may be prepared according to methods known tothose skilled in the art. For example, liposome formulations may beprepared as described in U.S. Pat. No. 4,522,811.

The active compound as salt, preferably as a sodium salt, is included inthe pharmaceutically acceptable carrier in an amount sufficient to exerta therapeutically useful effect in the absence of undesirable sideeffects on the patient treated. The therapeutically effectiveconcentration may be determined empirically by testing the compounds inknown in vitro and in vivo systems (see, e.g, U.S. Pat. No. 5,114,918 toIshikawa et al; EP Al 0 436 189 to BANYU PHARMACEUTICAL CO., LTD (Oct.7, 1991); Borges et al. (1989) Eur. J. Pharm. 165: 223-230;: Filep etal. (1991) Biochem. Biophys. Res. Commun. 177: 171-176) and thenextrapolated therefrom for dosages for humans.

The concentration of active compound sodium salt in the drug compositionwill depend on absorption, inactivation and excretion rates of theactive compound, the physicochemical properties of the active compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art. For example, the amount that isdelivered is sufficient to treat the symptoms of hypertension. Theeffective amounts for treating endothelin-mediated disorders areexpected to be higher than the amount of the sulfonamide compound thatwould be administered for treating bacterial infections.

Typically a therapeutically effective dosage should produce a serumconcentration of active ingredient of from about 0.1 ng/ml to about50-100 μg/ml. The pharmaceutical compositions typically should provide adosage of from about 0.001 mg to about 2000 mg of compound per kilogramof body weight per day. Pharmaceutical dosage unit forms are prepared toprovide from about 1 mg to about 1000 mg and preferably from about 10 toabout 500 mg of the essential active ingredient or a combination ofessential ingredients per dosage unit form.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

Preferred derivatives include acids, salts, esters and prodrug forms.The derivative is selected to be a more stable form than thecorresponding neutral compound. Preferred arepharmaceutically-acceptable salts, including, but not limited to, aminesalts, such as but not limited to N,N′-dibenzylethylenediamine,chloroprocaine, choline, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine, tris(hydroxymethyl)aminomethane,alkali metal salts, such as but not limited to lithium, potassium andsodium, alkali earth metal salts, such as but not limited to barium,calcium and magnesium, transition metal salts, such as but not limitedto iron, zinc, gold and silver, and other metal salts, such as but notlimited to aluminum, sodium hydrogen phosphate, disodium phosphate, orbismuth salts, preferably sodium salts, more preferably the sodium salt,and also including, but not limited to, salts of mineral acids, such asbut not limited to hydrochlorides and sulfates, salts of organic acids,such as but not limited to acetates, lactates, malates, tartrates,citrates, ascorbates, succinates, butyrates, valerates and fumarates ofthe sulfonamide compounds or pharmaceutically acceptable esters or otherderivatives thereof. More preferred salts include sodium salts, such as,but not limited to, a sodium hydrogen phosphate salt and a sodium salt,most preferably the sodium salt.

Thus, effective concentrations or amounts of one or more of thecompounds provided herein or pharmaceutically acceptable derivativesthereof are mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Compounds are included in an amount effective forameliorating or treating the endothelin-mediated disorder for whichtreatment is contemplated. The concentration of active compound in thecomposition will depend on absorption, inactivation, excretion rates ofthe active compound, the dosage schedule, amount administered,particular formulation as well as other factors known to those of skillin the art.

The compositions are intended to be administered by an suitable route,which includes orally, parenterally, rectally and topically and locallydepending upon the disorder being treated. For example, for treatment ofophthalmic disorders, such as glaucoma, formulation for intraocular andalso intravitreal injection is contemplated. For oral administration,capsules and tablets are presently preferred. For parenteraladministration reconstitution of a lyophilized powder, prepared asdescribed herein, is preferred. The compounds in liquid, semi-liquid orsolid form and are formulated in a manner suitable for each route ofadministration. Preferred modes of administration include parenteral andoral modes of administration.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent, such as water for injection, saline solution, fixedoil, polyethylene glycol, glycerine, propylene glycol or other syntheticsolvent; antimicrobial agents, such as benzyl alcohol and methylparabens; antioxidants, such as ascorbic acid and sodium bisulfite;chelating agents, such as ethylenediaminetetraacetic acid (EDTA);buffers, such as acetates, citrates and phosphates; and agents for theadjustment of tonicity such as sodium chloride or dextrose. Parenteralpreparations can be enclosed in ampules, disposable syringes or singleor multiple dose vials made of glass, plastic or other suitablematerial.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants,such as tween, or dissolution in aqueous sodium bicarbonate. Derivativesof the compounds, such as prodrugs of the compounds may also be used informulating effective pharmaceutical compositions.

Upon mixing or addition of the sodium salt of the sulfonamidecompound(s), the resulting mixture may be a solution, suspension,emulsion or the like. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe disease, disorder or condition treated and may be empiricallydetermined.

The formulations are provided for administration to humans and animalsin unit dosage forms, such as tablets, capsules, pills, powders, drypowders for inhalers, granules, sterile parenteral solutions orsuspensions, and oral solutions or suspensions, and oil-water emulsionscontaining suitable quantities of the compounds, particularly thepharmaceutically acceptable salts, preferably the sodium salts, thereof.The pharmaceutically therapeutically active compounds and derivativesthereof are typically formulated and administered in unit-dosage formsor multiple-dosage forms. Unit-dose forms as used herein refers tophysically discrete units suitable for human and animal subjects andpackaged individually as is known in the art. Each unit-dose contains apredetermined quantity of the therapeutically active compound sufficientto produce the desired therapeutic effect, in association with therequired pharmaceutical carrier, vehicle or diluent. Examples ofunit-dose forms include ampoules and syringes individually packagedtablet or capsule. Unit-dose forms may be administered in fractions ormultiples thereof. A multiple-dose form is a plurality of identicalunit-dosage forms packaged in a single container to be administered insegregated unit-dose form. Examples of multiple-dose forms includevials, bottles of tablets or capsules or bottles of pint or gallons.Hence, multiple dose form is a multiple of unit-doses which are notsegregated in packaging.

The composition can contain along with the active ingredient: a diluentsuch as lactose, sucrose, dicalcium phosphate, orcarboxymethylcellulose; a lubricant, such as magnesium stearate, calciumstearate and talc; and a binder such as starch, natural gums, such asgum acaciagelatin, glucose, molasses, polvinylpyrrolidine, cellulosesand derivatives thereof, povidone, crospovidones and other such bindersknown to those of skill in the art. Liquid pharmaceuticallyadministrable compositions can, for example, be prepared by dissolving,dispersing, or otherwise mixing an active compound as defined above andoptional pharmaceutical adjuvants in a carrier, such as, for example,water, saline, aqueous dextrose, glycerol, glycols, ethanol, and thelike, to thereby form a solution or suspension. If desired, thepharmaceutical composition to be administered may also contain minoramounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, or solubilizing agents, pH buffering agents and thelike, for example, acetate, sodium citrate, cyclodextrine derivatives,sorbitan monolaurate, triethanolamine sodium acetate, triethanolamineoleate, and other such agents. Actual methods of preparing such dosageforms are known, or will be apparent, to those skilled in this art; forexample, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 15th Edition, 1975. The composition or formulationto be administered will, in any event, contain a quantity of the activecompound in an amount sufficient to alleviate the symptoms of thetreated subject.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from non-toxic carrier may beprepared. For oral administration, a pharmaceutically acceptablenon-toxic composition is formed by the incorporation of any of thenormally employed excipients, such as, for example pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate, sodium saccharin, talcum. Such compositions includesolutions, suspensions, tablets, capsules, powders, dry powders forinhalers and sustained release formulations, such as, but not limitedto, implants and microencapsulated delivery systems, and biodegradable,biocompatible polymers, such as collagen, ethylene vinyl acetate,polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid andothers. Methods for preparation of these formulations are known to thoseskilled in the art. The contemplated compositions may contain 0.01%-100%active ingredient, preferably 0.1-95%, typically 75-95%.

The salts, preferably sodium salts, of the active compounds may beprepared with carriers that protect the compound against rapidelimination from the body, such as time release formulations orcoatings. The formulations may be include other active compounds toobtain desired combinations of properties. The compounds of formula I,or pharmaceutically acceptable salts and derivatives thereof asdescribed herein, may also be advantageously administered fortherapeutic or prophylactic purposes together with anotherpharmacological agent known in the general art to be of value intreating one or more of the diseases or medical conditions referred tohereinabove, such as beta-adrenergic blocker (for example atenolol), acalcium channel blocker (for example nifedipine), an angiotensinconverting enzyme (ACE) inhibitor (for example lisinopril), a diuretic(for example furosemide or hydrochlorothiazide), an endothelinconverting enzyme (ECE) inhibitor (for example phosphoramidon), aneutral endopeptidase (NEP) inhibitor, an HMGCoA reductase inhibitor, anitric oxide donor, an anti-oxidant, a vasodilator, a dopamine agonist,a neuroprotective agent, asteroid, a beta-agonist, an anti-coagulant, ora thrombolytic agent. It is to be understood that such combinationtherapy constitutes a further aspect of the compositions and methods oftreatment provided herein.

1. Formulations for Oral Administration

Oral pharmaceutical dosage forms are either solid, gel or liquid. Thesolid dosage forms are tablets, capsules, granules, and bulk powders.Types of oral tablets include compressed, chewable lozenges and tabletswhich may be enteric-coated, sugar-coated or film-coated. Capsules maybe hard or soft gelatin capsules, while granules and powders may beprovided in non-effervescent or effervescent form with the combinationof other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms,preferably capsules or tablets. The tablets, pills, capsules, trochesand the like can contain any of the following ingredients, or compoundsof a similar nature: a binder; an diluent; a disintegrating agent; alubricant; a glidant; a sweetening agent; and a flavoring agent.

Examples of binders include microcrystalline cellulose, gum tragacanth,glucose solution, acacia mucilage, gelatin solution, sucrose and starchpaste. Lubricants include talc, starch, magnesium or calcium stearate,lycopodium and stearic acid. Diluents include, for example, lactose,sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water soluble FD andC dyes, mixtures thereof; and water insoluble FD and C dyes suspended onalumina hydrate. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as sodium cyclamate and saccharin,and any number of spray dried flavors. Flavoring agents include naturalflavors extracted from plants such as fruits and synthetic blends ofcompounds which produce a pleasant sensation, such as, but not limitedto peppermint and methyl salicylate. Wetting agents include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurateand polyoxyethylene laural ether. Emetic-coatings include fatty acids,fats, waxes, shellac, ammoniated shellac and cellulose acetatephthalates. Film coatings include hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000 and cellulose acetatephthalate.

If oral administration is desired, the salt of the compound could beprovided in a composition that protects it from the acidic environmentof the stomach. For example, the composition can be formulated in anenteric coating that maintains its integrity in the stomach and releasesthe active compound in the intestine. The composition may also beformulated in combination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. Forexample, if the compound is used for treating asthma or hypertension, itmay be used with other bronchodilators and antihypertensive agents,respectively. The active ingredient is a compound or salt thereof asdescribed herein. Higher concentrations, up to about 98% by weight ofthe active ingredient may be included.

Pharmaceutically acceptable carriers included in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Enteric-coated tablets, because of theenteric-coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar-coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film-coated tablets are compressedtablets which have been coated with polymers or other suitable coating.Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents may also be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugar-coated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two-phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic adds and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicadd, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas sodium cyclamate and saccharin. Wetting agents include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurateand polyoxyethylene lauryl ether. Organic adds include citric andtartaric acid. Sources of carbon dioxide include sodium bicarbonate andsodium carbonate. Coloring agents include any of the approved certifiedwater soluble FD and C dyes, and mixtures thereof. Flavoring agentsinclude natural flavors extracted from plants such fruits, and syntheticblends of compounds which produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, eg.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g. water, tobe easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g. propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603.

In one embodiment, the formulations are solid dosage forms, preferablycapsules or tablets. In a preferred embodiment, the formulations aresolid dosage forms, preferably capsules or tablets, containing 10-100%,preferably 50-95%, more preferably 75-85%, most preferably 80-85%, byweight, of one or more sulfonamides or sulfonamide salts, preferablysodium hydrogen phosphate or sodium salts, more preferably the sodiumsalts, of one or more sulfonamide compounds of formula I; about 0-25%,preferably 8-15%, of a diluent or a binder, such as lactose ormicrocrystalline cellulose; about 0 to 10%, preferably about 3-7%, of adisintegrant, such as a modified starch or cellulose polymer,particularly a cross-linked sodium carboxymethyl cellulose, such ascrosscarmellose sodium (Crosscarmellose sodium NF is availablecommercially under the name AC—DI—SOL, FMC Corporation, Philadelphia,Pa.) or sodium starch glycolate; and 0-2% of a lubricant, such amagnesium stearate, talc and calcium stearate. The disintegrant, such ascrosscarmellose sodium or sodium starch glycolate, provides for rapidbreak-up of the cellulosic matrix for immediate release of active agentfollowing dissolution of coating polymer. In all embodiments, theprecise amount of active ingredient and auxiliary ingredients can bedetermined empirically and is a function of the route of administrationand the disorder that is treated.

In an exemplary embodiment, the formulations are capsules containingabout 80-90%, preferably about 83% of one or more sodium salts of one ormore sulfonamide compounds of formula I; about 10-15%, preferably about11% of a diluent or a binder, such as lactose or microcrystallinecellulose; about 1-10%, preferably about 5% of a disintegrant, such ascrosscarmellose sodium or sodium starch glycolate; and about 0.1 to 5%,preferably about 1% of a lubricant, such as magnesium stearate. Solidforms for administration as tablets are also contemplated herein.

In an exemplary preferred embodiment, the formulations are capsulescontaining 83% of one or more sodium salts of one or more sulfonamidecompounds; 11% of microcrystalline cellulose; 5% of a disintegrant, suchas Crosscarmellose sodium or sodium starch glycolate; and 1% ofmagnesium stearate.

The above embodiments may also be formulated in the form of a tablet,which may optionally be coated. Tablets will contain the compositionsdescribed herein.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

2. Injectables, Solutions and Emulsions

Parenteral administration, generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously is also contemplatedherein. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol orethanol. In addition, if desired, the pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins. Implantation of a slow-release or sustained-releasesystem, such that a constant level of dosage is maintained (see, e.g.,U.S. Pat. No. 3,710,795) is also contemplated herein. The percentage ofactive compound contained in such parenteral compositions is highlydependent on the specific nature thereof, as well as the activity of thecompound and the needs of the subject.

Parenteral administration of the formulations includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as the lyophilized powders describedherein, ready to be combined with a solvent just prior to use, includinghypodermic tablets, sterile suspensions ready for injection, sterile dryinsoluble products ready to be combined with a vehicle just prior to useand sterile emulsions. The solutions may be either aqueous ornonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (Tween 80). A sequestering or chelatingagent of metal ions include EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% wiw of the active compound to the treatedtissue(s). The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

It has been found that formulations containing certain sodium salts ofthe sulfonamides provided herein, particularly those in which R′ isphenylacetyl exhibit an increase in stability as compared toformulations containing the neutral compound. The data in Table 5reflects the increased stability of solutions of the sodium hydrogenphosphate and sodium salts of4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazoleas compared to the neutral compound. These salts also exhibit improvedsolubility over the neutral compound in aqueous media. As can be seenfrom Table 5, the sodium hydrogen phosphate salt is more stable than theneutral compound in a LABRASOL solution. The sodium salt was found, incertain aqueous formulations, to be as stable as the sodium hydrogenphosphate salt.

TABLE 5 SALT mg/mL VEHICLE h^(a) (%)^(b) none 150 LABRASOL 24 90.1sodium 100 LABRASOL 22.5 98.2 hydrogen 50.5 97.1 phosphate sodium 50 10%LABRASOL/water 6 87.0 hydrogen phosphate sodium 25 ″ 6 89.4 hydrogenphosphate sodium 100 DMSO 25 98.6 hydrogen phosphate sodium 10 0.01 MNaPO₄:PEG:EtOH (6:3:1) 24.5 98.6 hydrogen (pH 7.7) 48 100 phosphatesodium 2.4 water 17.5 96.5 hydrogen phosphate sodium 25 0.1% BSA inwater 92 46.6 hydrogen phosphate sodium 25 water 6 94.5 hydrogenphosphate sodium 10 water:PEG 400:EtOH (6:3:1) 6 100 hydrogen phosphatesodium 10 0.01 M NaPO₄:PEG 400:EtOH 67.5 100 hydrogen (6:3:1) (pH 7.5) 7 days 98.8 phosphate 19 days 95.6 sodium 5 deionized water 24 93hydrogen 48 85 phosphate 72 77 sodium 5 tap water 24 91 hydrogen 38 84phosphate 72 76 sodium 0.51 normal saline 24 96.9 ″ ″ 5% dextrose 2499.4 ″ 0.57 0.75% PVP + 1.5% PG 24 74.4 ″ 0.49 1.5% PVP + 3.0% PG 2490.0 ″ 100 5% dextrose 6 93.0 ″ 100 30% sorbitol 24 93.2 ″ 30 5%dextrose 24 92.2 ″ 30 20% sorbitol 24 93.2 ″ 20 5% dextrose 24 92.4 ″ 2010% dextrose 24 93.4 ″ 20 10% dextrose + 10% PG 24 95.6 ″ 20 5% dextrose24 93.7 (13° C.)  ″ 20 5% dextrose 24 90.1 ″ 20 5% dextrose +K-phosphate 20 92.6 buffer, 2.5% w/v (pH 7) ″ 20 5% dextrose +K-phosphate 24 89.4 buffer, 2.5% w/v (pH 6.5) ″ ″ 5% dextrose +K-phosphate 24 84.6 buffer, 2.5% w/v (pH 6) ″ ″ 5% dextrose +K-phosphate ″ 93.4 buffer, 2.5% w/v (pH 7.5) ″ ″ 5% dextrose + citratebuffer, 21 92.9 0.3% w/v (pH 8) ″ ″ 10% dextrose + 10% PG + 24 90.7Na-phosphate buffer, 0.3% w/v (pH 7.5) ″ 10% dextrose + 10% PG + 24 97.4Na-phosphate buffer, 0.3% w/v (4° C.) (pH 7.5) ″ 10% dextrose + 10% PG +24 96.4 Na-phosphate buffer, 0.3% w/v (4° C.) (pH 8) ″ 10% dextrose +10% PG + 24 97.6 citrate buffer, 0.3% w/v (pH (4° C.) 7.4) ″ 10%dextrose + 10% PG 24 97.6 ″ (4° C.) ″ 30 10% dextrose + 10% PG + 24 98.0citrate buffer, 0.3% w/v (pH (4° C.) 7.5) ″ 20 5% dextrose + 5% PG + 2697.2 citrate buffer, 0.3% w/v (pH (4° C.) 7.5) ″ 100 10% dextrose +10%PG + 24 94.2 citrate buffer, 0.3% w/v (pH 7.5) ″ 20 5% dextrose +citrate buffer, 27 96.6 0.3% w/v (pH 7.5) (4° C.) ″ 100 30% sorbitol 2493.2 ″ 30 5% dextrose 24 92.2 ″ 30 20% sorbitol 24 93.2 ″ 20 5% dextrose24 92.4 ″ 20 10% dextrose 24 93.4 ″ 20 10% dextrose + 10% PG 24 95.6 ″20 5% dextrose 24 90.2 ″ 20 5% dextrose 25 93.7 (10° C.)  ″ 20 5%dextrose + 5% buffer (pH 24 92.6 7.0) ^(a)hours following preparation ofthe formulation ^(b)percent4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazoleremaining as determined by high performance liquid chromatographicanalysis.

In many instances, the solutions of sodium salts, including the sodiumsalt and sodium hydrogen phosphate salts exhibit improved stability ascompared to the neutral compound. These salts also exhibit improvedsolubility over the neutral compound in aqueous media.

3. Lyophilized Powders

Of particular interest herein, are lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be formulated as solids or gels.

In particular embodiments, formulations of sodium hydrogen phosphate orsodium, preferably sodium, salts of the sulfonamide compounds, whichpossess increased stability relative to formulations of the neutralsulfonamides are provided. Specifically, formulation of sulfonamidesodium salts as a sterile, lyophilized powder are provided. Thesepowders were found to have increased stability relative to formulationsof the neutral sulfonamides.

The sterile, lyophilized powder is prepared by dissolving the sodiumsalt in a sodium phosphate buffer solution containing dextrose or othersuitable excipient. Subsequent sterile filtration of the solutionfollowed by lyophilization under standard conditions known to those ofskill in the art provides the desired formulation. Briefly, thelyophilized powder is prepared by dissolving dextrose, sorbitol,fructose, corn syrup, xylitol, glycerin, glucose, sucrose or othersuitable agent, about 1-20%, preferably about 5 to 15%, in a suitablebuffer, such as citrate, sodium or potassium phosphate or other suchbuffer known to those of skill in the art at, typically, about neutralpH. Then, a selected salt, preferably the sodium salt of the sulfonamide(about 1 g of the salt per 10-100 g of the buffer solution, typicallyabout 1 g/30 g), is added to the resulting mixture, preferably aboveroom temperature, more preferably at about 30-35° C., and stirred untilit dissolves. The resulting mixture is diluted by adding more buffer (sothat the resulting concentration of the salt decreases by about 10-50%,typically about 1 5-25%). The resulting mixture is sterile filtered ortreated to remove particulates and to insure sterility, and apportionedinto vials for lyophilization. Each vial will contain a single dosage(100-500 mg, preferably 250 mg) or multiple dosages of the sulfonamidesalt. The lyophilized powder can be stored under appropriate conditions,such as at about 4° C. to room temperature. Details of an exemplaryprocedure are set forth in the Examples.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration of sodiumsalts of the sulfonamides. For reconstitution about 1-50 mg, preferably5-35, more preferably about 9-30 is added per ml of sterile water orother suitable carrier. The precise amount depends upon the indicationtreated and selected compound. Such amount can be empiricallydetermined.

In one embodiment, the formulations contain lyophilized solidscontaining one or more sodium hydrogen phosphate or sodium, preferablysodium, salts of one or more sulfonamide compounds of formula 1, andalso contain one or more of the following:

a buffer, such as sodium or potassium phosphate, or citrate;

a solubilizing agent, such as LABRASOL, DMSO,bis(trimethylsilyl)acetamide, ethanol, propyleneglycol (PG), orpolyvinylpyrrolidine (PVP); and

a sugar or carbohydrate, such as sorbitol or dextrose.

In more preferred embodiments, the formulations contain one or moresodium hydrogen phosphate or sodium, preferably sodium, salts of one ormore sulfonamide compounds of formula l; a buffer, such as sodium orpotassium phosphate, or citrate; and a sugar or carbohydrate, such assorbitol or dextrose.

In the most preferred embodiments, the formulations contain one or moresodium salts of the sulfonamide compounds; a sodium phosphate buffer;and dextrose. The preparation of these formulations is exemplified inthe EXAMPLES.

4. Topical Administration

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The sodium salts and other derivatives of the compounds may beformulated as aerosols for topical application, such as by inhalation(see, e.g. U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, whichdescribe aerosols for delivery of a steroid useful for treatment ofinflammatory diseases, particularly asthma). These formulations foradministration to the respiratory tract can be in the form of an aerosolor solution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the formulation will typically diameters of lessthan 50 microns, preferably less than 10 microns.

The sodium salts of the compounds may be formulated for local or topicalapplication, such as for topical application to the skin and mucousmembranes, such as in the eye, in the form of gels, creams, and lotionsand for application to the eye or for intracisternal or intraspinalapplication. Topical administration is contemplated for transdermaldelivery and also for administration to the eyes or mucosa, or forinhalation therapies. Nasal solutions of the active compound alone or incombination with other pharmaceutically acceptable excipients can alsobe administered.

These solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts.

5. Articles of Manufacture

The derivatives, particularly the salts, acids, esters and preferablythe sodium salts of the compounds may be packaged as articles ofmanufacture containing packaging material, a sodium salt of a compoundprovided herein, which is effective for antagonizing the effects ofendothelin, ameliorating the symptoms of an endothelin-mediateddisorder, or inhibiting binding of an endothelin peptide to an ETreceptor with an IC₅₀ of less than about 10, μM, within the packagingmaterial, and a label that indicates that the compound or salt thereofis used for antagonizing the effects of endothelin, treatingendothelin-mediated disorders or inhibiting the binding of an endothelinpeptide to an ET receptor.

6. Formulations for Other Routes of Administration

Depending upon the condition treated other routes of administration,such as topical application, transdermal patches, an rectaladministration are also contemplated herein.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax,(polyoxyethylene glycol) and appropriate mixtures of mono-, di- andtriglycerides of fatty acids. Combinations of the various bases may beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories may be prepared either by thecompressed method or by molding. The typical weight of a rectalsuppository is about 2 to 3 gm.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

E. Evaluation of the Bioactivity of the Compounds

Standard physiological, pharmacological and biochemical procedures areavailable for testing the compounds to identify those that possess anybiological activities of an endothelin peptide or the ability tointerfere with or inhibit endothelin peptides. Compounds that exhibit invitro activities, such as the ability to bind to endothelin receptors orto compete with one or more of the endothelin peptides for binding toendothelin receptors can be used in the methods for isolation ofendothelin receptors and the methods for distinguishing thespecificities of endothelin receptors, and are candidates for use in themethods of treating endothelin-mediated disorders.

Thus, other preferred compounds of formulas I and II, in addition tothose specifically identified herein, that are endothelin antagonists oragonists may be identified using such screening assays.

1. Identifying Compounds that Modulate the Activity of an EndothelinPeptide

The compounds are tested for the ability to modulate the activity ofendothelin-1. Numerous assays are known to those of skill in the art forevaluating the ability of compounds to modulate the activity ofendothelin (see, e.g., U.S. Pat. No. 5,114,918 to Ishikawa et al.; EP A10 436 189 to BANYU PHARMACEUTICAL CO., LTD. (Oct. 7, 1991); Borges etal. (1989) Eur. J. Pharm. 165:223-230; Filep et al. (1991) Biochem.Biophys. Res. Commun. 177: 171-176). In vitro studies may becorroborated with in vivo studies (see, e.g., U.S. Pat. No. 5,114,918 toIshikawa et al.; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD.(October 7, 1991)) and pharmaceutical activity thereby evaluated. Suchassays are described in the Examples herein and include the ability tocompete for binding to ET_(A) and ET_(B) receptors present on membranesisolated from cell lines that have been genetically engineered toexpress either ET_(A) or ET_(B) receptors on their cell surfaces.

The properties of a potential antagonist may be assessed as a functionof its ability to inhibit an endothelin induced activity in vitro usinga particular tissue, such as rat portal vein and aorta as well as ratuterus, trachea and vas deferens (see e.q., Borges, R., Von Grafenstein,H. and Knight, D. E., “Tissue selectivity of endothelin,” Eur. J.Pharmacol 165:223-230, (1989)). The ability to act as an endothelinantagonist in vivo can be tested in hypertensive rats, ddy mice or otherrecognized animal models (see, Kaltenbronn et al. (1990) J. Med. Chem.33:838-845, see, also, U.S. Pat. No. 5,114,918 to Ishikawa et al.; andEP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD (Oct. 7, 1991); see,also Bolger et al. (1983) J. Pharmacol. Exp. Ther. 225291-309). Usingthe results of such animal studies, pharmaceutical effectiveness may beevaluated and pharmaceutically effective dosages determined. A potentialagonist may also be evaluated using in vitro and in vivo assays known tothose of skill in the art.

Endothelin activity can be identified by the ability of a test compoundto stimulate constriction of isolated rat thoracic aorta (Borges et al.(1989) “Tissue selectivity of endothelin” Eur. J. Pharmacol.165:223-230). To perform the assay, the endothelium is abraded and ringsegments mounted under tension in a tissue bath and treated withendothelin in the presence of the test compound. Changes in endothelininduced tension are recorded. Dose response curves may be generated andused to provide information regarding the relative inhibitory potency ofthe test compound. Other tissues, including heart, skeletal muscle,kidney, uterus, trachea and vas deferens, may be used for evaluating theeffects of a particular test compound on tissue contraction.

Endothelin isotype specific antagonists may be identified by the abilityof a test compound to interfere with endothelin binding to differenttissues or cells expressing different endothelin-receptor subtypes, orto interfere with the biological effects of endothelin or an endothelinisotype (Takayanagi et al. (1991) Reg. Pep. 32:23-37, Panek et al.(1992) Biochem. Biophys. Res. Commun. 183:566-571). For example, ET_(B)receptors are expressed in vascular endothelial cells, possiblymediating the release of prostacyclin and endothelium-derived relaxingfactor (De Nucci et al. (1988) Proc. Natl. Acad. Sci. USA 85:9797).ET_(A) receptors are not detected in cultured endothelial cells, whichexpress ET_(B) receptors.

The binding of compounds or inhibition of binding of endothelin toET_(B) receptors can be assessed by measuring the inhibition ofendothelin-1-mediated release of prostacyclin, as measured by its majorstable metabolite, 6-keto PGF_(1α), from cultured bovine aorticendothelial cells (see, e.g., Filep et al. (1991) Biochem. and BiophysRes. Commun. 177:171-176). Thus, the relative affinity of the compoundsfor different endothelin receptors may be evaluated by determining theinhibitory dose response curves using tissues that differ in receptorsubtype.

Using such assays, the relative affinities of the compounds for ET_(A)receptors and ET_(B) receptors have been and can be assessed. Those thatpossess the desired properties, such as specific inhibition of bindingof endothelin-1, are selected. The selected compounds that exhibitdesirable activities may be therapeutically useful and are tested forsuch uses using the above-described assays from which in vivoeffectiveness may be evaluated (see, e.g., U.S. Pat. No. 5,248,807; U.S.Pat. No. 5,240,910; U.S. Pat. No. 5,198,548; U.S. Pat. No. 5,187,195;U.S. Pat. No. 5,082,838; U.S. Pat. No. 5,230,999; published CanadianApplication Nos. 2,067,288 and 2071193; published Great BritainApplication No. 2,259,450; Published International PCT Application No.WO 93/08799; Benigi et al. (1993) Kidney International 44:440-444; andNirei et al. (1993) Life Sciences 52:1869-1874). Compounds that exhibitin vitro activities that correlate with in vivo effectiveness will thenbe formulated in suitable pharmaceutical compositions and used astherapeutics.

The compounds also may be used in methods for identifying and isolatingendothelin-specific receptors and aiding in the design of compounds thatare more potent endothelin antagonists or agonists or that are morespecific for a particular endothelin receptor.

2. Isolation of Endothelin Receptors

A method for identifying endothelin receptors is provided. In practicingthis method, one or more of the compounds is linked to a support andused in methods of affinity purification of receptors. By selectingcompounds with particular specificities, distinct subclasses of ETreceptors may be identified.

One or more of the compounds may be linked to an appropriate resin, suchas Affi-gel, covalently or by other linkage, by methods known to thoseof skill in the art for linking endothelin to such resins (see, Schvartzet al. (1990) Endocrinology 126: 3218-3222). The linked compounds can bethose that are specific for ET_(A) or ET_(B) receptors or other subclassof receptors.

The resin is pre-equilibrated with a suitable buffer generally at aphysiological pH (7 to 8). A composition containing solubilizedreceptors from a selected tissue are mixed with the resin to which thecompound is linked and the receptors are selectively eluted. Thereceptors can be identified by testing them for binding to an endothelinisopeptide or analog or by other methods by which proteins areidentified and characterized. Preparation of the receptors, the resinand the elution method may be performed by modification of standardprotocols known to those of skill in the art (see, e.g, Schvartz et al.(1990) Endocrinology 126:3218-3222).

Other methods for distinguishing receptor type based on differentialaffinity to any of the compounds herein are provided. Any of the assaysdescribed herein for measuring the affinity of selected compounds forendothelin receptors may also be used to distinguish receptor subtypesbased on affinity for particular compounds provided herein. Inparticular, an unknown receptor may be identified as an ET_(A) or ET_(B)receptor by measuring the binding affinity of the unknown receptor for acompound provided herein that has a known affinity for one receptor overthe other. Such preferential interaction is useful for determining theparticular disease that may be treated with a compound prepared asdescribed herein. For example, compounds with high affinity for ET_(A)receptors and little or no affinity for ET_(B) receptors are candidatesfor use as hypertensive agents; whereas, compounds that preferentiallyinteract with ET_(B) receptors are candidates for use as anti-asthmaagents.

The following examples are included for illustrative purposes only andare not intended to limit the scope of the invention.

EXAMPLE 1

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene-3-sulfonamide

Carbonydiimidazole (485 mg, 2.99 mmol) was added to a solution ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide (1g, 2.72 mmol) in THF (10 ml) at room temperature. The mixture wasstirred for 15 minutes. Aqueous NH₃ (5 ml) was then added, and themixture was stirred at room temperature for 30 minutes. The solvent wasevaporated and the residue was partitioned between EtOAc and 1 N HCl.The organic layer was dried (MgSO₄). The solid was filtered and thefiltrate concentrated. The oily residue was recrystallized from EtOAc togiveN-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene-3-sulfonamide(946 mg, 95% yield) as a white solid, m.p. 168-170° C.

EXAMPLE 2

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzoyl]thiophene-3-sulfonamide

A.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-methoxy-N-methyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-methoxy-N-methyl)carboxamide]thiophene-3-sulfonamidewas prepared by the same method as described in Example 1 with theexception that N,O-dimethylhydroxylamine was used in place of ammoniumhydroxide. The yield was 90%.

B.N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzoyl]thiophene-3-sulfonamide

Freshly prepared (3,4-methylenedioxy)phenyl magnesium bromide (1.28 g of(3,4-methylenedioxy)bromobenzene and 172 mg Mg turnings) was added to asolution ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-methoxy-N-methyl)aminocarbonyl]thiophene-3-sulfonamide(A) (652 mg, 1.59 mmol) in THF (10 ml) at room temperature. Theresulting mixture was refluxed for 30 minutes. To workup, the mixturewas allowed to cool to room temperature and was quenched with 1N HCl (10ml). THF was then evaporated. The aqueous residue was partitionedbetween 1 N HCl and EtOAc. The organic layer was concentrated and theresidue was purified by HPLC to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzoyl]thiophene-3-sulfonamide(90 mg, 12% yield) as a dark yellow powder, m.p. 47-490 C.

EXAMPLE 3

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(2-hydroxyphenyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-hydroxyphenyl)aminocarbonyl]-thiophene-3-sulfonamidewas prepared by the same method as described in Example 1 with theexception that 3-aminophenol was used in place of ammonium hydroxide.The product was purified by HPLC to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-hydroxyphenyl)aminocarbonyl]thiophene-3-sulfonamide(50 mg, 18% yield) as a dull yellow solid, m.p. 42-44° C.

EXAMPLE 4

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylacetylthiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylacetyl]thiophene-3-sulfonamidewas prepared by the same method as described in Example 2 with theexception that piperonylmagnesium chloride was used instead of(3,4-methylenedioxy)phenylmagnesium bromide and the reaction mixture wasstirred overnight at room temperature instead of refluxing for 30minutes. The crude mixture was purified by HPLC to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide(20 mg, 40% yield) as a yellow oil.

EXAMPLE 5

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylacetyl]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylacetyl]-thiophene-3-sulfonamidewas prepared by the same method as described in Example 4 with theexception thatN-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide wasused instead ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylacetyl]thiophene-3-sulfonamide(3 g, 50% yield) was obtained via HPLC purification as a yellow solid,m.p. 35-38° C.

EXAMPLE 6

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenyl-acetyl-3-thiophenesulfonamidealso designated4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazoleandN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide

A. (3,4-methylenedioxy)-6-methylbenzyl chloride

To a 1:1 mixture of ethyl ether (100 ml) and conc. HCl (100 ml) at 0° C.was added (3,4-methylenedioxy)toluene (10 ml). Formaldehyde (20 ml, 37%in water) was then added dropwise. The reaction was stirred at 0° C. for2 hours and at room temperature for an additional 10 hours. The reactionmixture was then diluted with ethyl ether (100 ml) and the two layerswere separated. The organic layer was dried (MgSO₄), the solid wasfiltered and the filtrate was concentrated. The residue was then heatedwith hexane (200 ml) and the insolubles were filtered off the hotsolution. The filtrate was concentrated to give a mixture of(3,4-methylenedioxy)-6-methylbenzyl chloride (9.4 g, 63% yield) andbis[(3,4-methylenedioxy)-6-methyl]phenylmethane (3.6 g) as a whitesolid. This mixture was carried on to the next step without furtherpurification.

B.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 5 using(3,4-methylenedioxy)-6-methylbenzyl chloride instead of(3,4-methylenedioxy)benzyl chloride. The crude product was purified bypreparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamideas a yellow powder (71% yield, m.p. 42-45° C.).

EXAMPLE 7

4-Chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole,Sodium Salt

A. Preparation of(4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole

1. Preparation of 5-chloromethyl-6-methylbenzo[d][1,3]dioxole

To a mixture of methylene chloride (130 L), concentrated HCl (130 L),and tetrabutylammonium bromide (1.61 Kg) was added 5methylbenzo[d][1,3]dioxole (10 Kg) followed by the slow addition offormaldehyde (14 L, 37 wt % in water). The mixture was stirredovernight. The organic layer was separated, dried with magnesium sulfateand concentrated to an oil. Hexane (180 L) was added and the mixtureheated to boiling. The hot hexane solution was decanted from a heavyoily residue and evaporated to give almost pure5-chloromethyl-6-methylbenzo[d][1,3]dioxole as a white solid.Recrystallization from hexane (50 L) gave5-chloromethyl-6-methylbenzo[d][1,3]dioxole (80% recovery afterrecrystallization).

2. Formation of(4-chloro-3-methyl-5-(2-(2-(2-methylbenzofd][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole

A portion of a solution of 5-chloromethyl-6-methylbenzo[d][1,3]dioxole(16.8 g, 0.09 mol) in tetrahydrofuran (THF)(120 mL) was added to a wellstirred slurry of magnesium powder, (3.3 g, 0.136 g-atom, Alfa, orJohnson-Matthey,—20+100 mesh) in THF (120 mL) at room temperature. Theresulting reaction admixture was warmed up to about 40-45° C. for about2-3 min, causing the reaction to start. Once the magnesium was activatedby the heating, and the reaction begun, the mixture was cooled andmaintained at a temperature below about 8° C. The magnesium can beactivated with dibromoethane in place of heat.

A flask containing the reaction mixture was cooled and the remainingsolution of 5-chloromethlybenzo[d][1,3]dioxole added dropwise during 1.5hours while maintaining an internal temperature below 8° C. Temperaturecontrol is important: if the Grignard is generated and kept below 8° C.,no Wurtz coupling takes place. Longer times at higher temperaturespromote the Wurtz coupling pathway. Wurtz coupling can be avoided byusing high quality Mg and by keeping the temperature of the Grignardbelow about 8° C. and stirring vigorously. The reaction works fine at−20° C., so any temperature below 8° C. is acceptable at which theGrignard will form. The color of the reaction mixture turns greenish.

The reaction mixture was stirred for an additional 5 min at 0° C., whileN²-methoxy-N²-methyl-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide(6.6 g, 0.018 mol) in anhydrous THF (90 mL) was charged into theaddition funnel. The reaction mixture was degassed two times then thesolution ofN²-methoxy-N²-methyl-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamidewas added at 0° C. over 5 min. TLC of the reaction mixture (Silica, 12%MeOH/CH₂Cl₂) taken immediately after the addition shows noN²-methoxy-N²-methyl-3-(4-chloro-3-methyl-5-isoxazolysulfamoyl)-2-thiophenecarboxamide.

The reaction mixture was transferred into a flask containing 1 N HCl(400 mL, 0.4 mol HCl, ice-bath stirred), and the mixture stirred for 2to 4 min, transferred into a separatory funnel and diluted with ethylacetate (300 mL). The layers were separated after shaking. The waterlayer was extracted with additional ethyl acetate (150 mL) and thecombined organics washed with half-brine. Following separation, THF wasremoved by drying the organic layer over sodium sulfate andconcentrating under reduced pressure at about 39° C.

B. Preparation of4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole,Sodium Salt

The product from part A was then re-dissolved in ethyl acetate andwashed with saturated NaHCO₃ (5×50 mL) until the washings becamecolorless. The solution was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give a semicrystalline yellow residue. 100 mLof CH₂Cl₂ was added to the solution and the mixture stirred undernitrogen for from 5 to 10 minutes until a fine crystalline product wasformed. Ether (150 mL) was added and the mixture stirred from anappropriate time (e.g., 10 min). The product was isolated by filtration,washed with a mixture of CH₂Cl₂/ether (1:2) (30 mL) then with ether (30mL) and dried under reduced pressure. When prepared in accordance withthe specific embodiments set forth above, the title product was producedin quantity of 7.3 g with a purity of around 85% (HPLC, RP, 40%acetonitrile/water, 0.1% TFA neutralized with ammonia to pH 2.5,isocratic conditions, 1 mL/min).

The salt product from above was dissolved in water (600 mL) at 10° C.,the solution stirred for a short period of time (e.g., 3 min) and thenfiltered through a layer of paper filters (e.g., 3 filters) withsuction. In some cases, the large amount of impurities that are notsoluble in water (10% or higher) slows down the filtration processextremely. This problem can be avoided by using a larger size filterduring the filtration. Usually there is no problem with filtration ifthe purity of the crude salt is 90% or higher.

The greenish slightly turbid solution obtained from filtration wascooled in an ice bath and acidified to a pH of 2 using an acid such as 4N HCl. When the pH of the solution was 2, the product precipitates as amilky, non-filterable material. Slow dropwise addition of extra 4 N HClcauses the product to form a fine, easily filterable precipitate. Thepale yellow precipitate was filtered off, washed with water untilneutral and pressed on the filter to get rid of excess of water). Theobtained free acid was typically 95% pure as determined by HPLC.

The free acid form of the product was dissolved in ethyl acetate (about100 mL), washed with brine (30 mL) to remove water. The dehydratedsolution was shaken with cold saturated NaHCO₃ solution (2×30 mL), thenwith brine again, dried over Na₂SO₄ and concentrated in vacuo (bathtemperature lower than 40° C.) to give a very bright yellow foam. Aftercomplete removal of the ethyl acetate from this product, CH₂Cl₂ (100 mL)was added and the mixture stirred for 5 to 10 min until the productbecame crystalline. Ether (150 mL) was added and stirring continued for10 min longer. The formed solid was isolated by filtration, washed witha mixture of CH₂Cl₂/ether (1:2)(30 mL) then with ether (30 mL) and driedunder reduced pressure. When purified in this manner,4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsufonamido)isoxazole,sodium salt was obtained in high yield (5.7 g, 68%) with good purity(98.2% pure by HPLC). The product can also be further purified byrecrystallization from EtOH/methyl t-butylether (MTBE) after the aboveprocedure if the initial purity is sufficiently high.

C.N-(4-Chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]-phenylacetyl-3-thiophenesulfonamide,Sodium Hydrogen Phosphate Salt also Designated4-Chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole,Sodium Hydrogen Phosphate Salt

To a solid mixture ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamide(1.1492 g, 2.5263 mmol) and sodium phosphate dibasic (0.3486 g, 2.5263mmol) was added de-ionized water (25 mL) and acetonitrile (25 mL). Theresulting mixture was well shaken and warmed at 50° C. to obtain a clearsolution, which was filtered. The filtrate was frozen at −78° C. andlyophilized to give the salt as a yellow powder (≈1.50 g).

EXAMPLE 8

Formulations of Sulfonamide Sodium Salts as Lyophilized Powder

Formulation of 4-chloro-3-methyl-5-(2-(2-(6-methylbenzo [d][1,3]dioxol-5-yl)ace-tyl)-3-thienylsulfonamido)isoxazole, Sodium Saltfor Parenteral Administration

Phosphate buffer was prepared by adding 3200 mL of sterile water forinjection, USP, to a 4 L graduated cylinder. Sodium phosphate dibasicheptahydrate, USP (21.44 g) was added to the sterile water and themixture was stirred for 5 minutes or until the solid had dissolved.Sodium phosphate monobasic, USP (11.04 g) was added and the mixture wasstirred until the solids had dissolved. The solution was diluted to 4.0L and stirred. 3000 g of the sodium phosphate buffer was added to aneight liter beaker. Dextrose, USP (200.0 g) was added, and the mixturewas heated to 30-35° C. in a water bath and stirred until a completesolution formed.4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole,sodium salt (100.0 g) was added with efficient mixing. This mixture wasstirred for a minimum of ten minutes or until a solution formed.

The solution was removed from the water bath after the sodium saltdissolved, diluted to 4000 g with sodium phosphate buffer and stirredfor five minutes. This solution was sterile filtered using a sterile0.22 micron pre-size Durapore Millipak 200 filter. The filtered solutionwas filled into sterile vials and lyophilized under standard conditions.The vials were stoppered. The lyophilized product was then reconstitutedwith either 9.4 mL or 19.4 mL of water for injection, to give a finalconcentration of 25 mg/mL or 12.5 mg/mL, respectively.

EXAMPLE 9

N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide

A solution of 5-amino-4-bromo-3-methylisoxazole (1 77 mg, 1.0 mmol) indry tetrahydrofuran (THF, 2 ml) was added to a suspension of sodiumhydride (60% dispersion in mineral oil, 90 mg, 2.2 mmol) in dry THF (1ml) at 0-5° C. After stirring at 0-5° C. for 5 min., the reaction wasstirred at room temperature for 10 min to complete the reaction. Thereaction mixture was re-cooled to 0° C. and thiophene-2-sulfonylchloride (200 mg, 1.1 mmol) dissolved in dry THF (2 ml) was addeddropwise. Stirring was continued for 1 h; during this period thereaction mixture slowly attained ambient temperature. THF was removedunder reduced pressure. The residue was dissolved in water (10 ml), thepH was adjusted to 10-11 by adding 5 N sodium hydroxide solution, andwas extracted with ethyl acetate (3×10 ml) to remove the neutralimpurities. The aqueous layer was acidified with concentrated HCl (pH2-3) and extracted with methylene chloride (3×10 ml). The combinedorganic layers was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to giveN-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide. The purematerial was obtained by recrystallization using hexanes/ethyl acetate(110 mg, 34% yield), m.p. 125-127° C.

EXAMPLE 10

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-isoxazolyl)thiophene-2-sulfonamide

A solution of 5-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mmol) indry THF (2 ml) was added to a suspension of sodium hydride (60%dispersion in mineral oil, 90 mg, 2.2 mmol) in dry THF (1 ml) at 0-5° C.After stirring at 0-5° C. for 5 min, the reaction was warmed to roomtemperature for 10 min to complete the reaction. The reaction mixturewas re-cooled to 0° C, and 5-(3-isoxazolyl)thiophene-2-sulfonyl chloride(273 mg, 1.1 mmol), which had been dissolved in dry THF (2 ml), wasadded slowly. Stirring was continued for 1 h; during this period thereaction mixture slowly attained ambient temperature. THF was removedunder reduced pressure. The residue was dissolved in water (10 ml), thepH was adjusted to 2-3 by adding concentrated HCl, and was extractedwith methylene chloride (3×10 ml). The combined organic layers was driedover anhydrous magnesium sulfate and concentrated under reduced pressureto giveN-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-isoxazolyl)thiophene-2-sulfonamide.The pure material was obtained by recrystallization using hexanes/ethylacetate (160 mg, 41% yield), m.p. 120-123° C.

EXAMPLE 11

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamidewas prepared in the same manner as described in Example 10 from5-amino-4-bromo-3-methylisoxazole and2-(carbomethoxy)thiophene-3-sulfonyl chloride in 73% yield. Purificationwas achieved by recrystallization from ethyl acetate/hexanes to give acrystalline solid, m.p. 198-200° C.

EXAMPLE 12

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide(Example 11) (1.5 g, 3.95 mmol) was dissolved in methanol (10 ml).Sodium hydroxide pellets (1 g, 25 mmol) and a few drops of water werethen added. The resultant solution was stirred for 16 h at ambienttemperature. Methanol was removed under reduced pressure. The residuewas diluted with water and was extracted with ethyl acetate (2×10 ml).The aqueous layer was acidified (pH=2) with concentrated hydrochloricacid and was extracted with ethyl acetate (2×60 ml). The combinedorganic layers was dried over anhydrous magnesium sulfate and filtered.Removal of the solvent gaveN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide(1.2 g, 82% yield), which was purified by silica gel columnchromatography using ethyl acetate as eluent, m.p. 188-194° C.

EXAMPLE 13

N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide

A. N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide

A solution of 5-bromothiophene-2-sulfonyl chloride (2.75 g, 10 mmol) and5-amino-3,4-dimethylisoxazole (1.07 g, 9.57 mmol) in pyridine containinga catalytic amount of 4-dimethylaminopyridine (DMAP, 10 mg) was stirredat room temperature for a period of 3 h. The solution was heated at 50°C. for an additional 1.5 h to drive the reaction to completion as judgedby TLC. The pyridine was removed under reduced pressure and the residue,after extraction into ethyl acetate, was washed with 1 N HCl (2×25 ml),water (1×25), brine solution, (1×25 ml) and dried over magnesiumsulfate. Evaporation of solvent left a viscous brown gum, which wassubjected to flash chromatography. Elution with 3% methanol hexanes gave246 mg (10%) of pure sulfonamide.

B.N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (680 mg, 2mmol) in dry THF (2 ml) was added to sodium hydride (1 21 mg of a 60%oil dispersion, 3 mmol) in dry THF (1 ml). The resulting suspension wascooled to 0° C. and methoxyethoxymethyl chloride (334 mg, 2.68 mmol) wasadded dropwise via syringe. The solution was warmed to room temperature,and stirring continued overnight. Evaporation of solvent left an oilthat was extracted into ethyl acetate, washed with brine, dried overmagnesium sulfate and evaporated. Flash chromatography of the residue onsilica gel using 10-15% ethyl acetate/hexanes yielded 480 mg (56%) of acolorless oil.

C.N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide

Sodium carbonate (2 ml of a 2 M aqueous solution) followed by phenylboronic acid (86 mg, 0.71 mmol) in 2 ml of 95% ethanol were added to asolution ofN-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide(200 mg, 0.47 mmol) and tetrakis (triphenylphosphine) palladium (0) (23mg, 0.02 mmol) in dry benzene (4 ml) under argon. The mixture wasrefluxed for 12 h, diluted with 5 ml of water and extracted into ethylacetate (3×25 ml). The combined organic extracts was washed with brine(1×25 ml), dried and evaporated. The residue was flash chromatographedon silica gel using 25% ethyl acetate/hexanes to afford 1 23 mg (62%) ofthe sulfonamide as a colorless gum.

D. N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide

HCl (3 ml of a 3 N aqueous solution) was added to a solution ofN-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide(100 mg, 0.24 mmol) in 3 ml of 95% ethanol and the resulting mixture wasrefluxed for 6 h. The mixture was then concentrated, diluted with 5 mlof water, neutralized with saturated aqueous sodium bicarbonate solutionand acidified to pH 4 using glacial acetic acid. The mixture wasextracted with ethyl acetate (2×25 ml) and the combined organic extractwas washed with brine (1×5 ml), dried and evaporated. Flashchromatography of the residue on silica gel using 2% MeOH/CHCl₃ andfurther purification by reverse phase HPLC yielded 33.4 mg (42%) of thepure sulfonamide as a white powder, m.p. 176-178° C.

EXAMPLE 14

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2-sulfonamide

A. N-(5-bromothiophene-2-sulfonyl)-pyrrole

Sodium hydride (60% oil dispersion, 191 m.g., 4.78 mmol) was suspendedin dry tetrahydrofuran (2 ml) and the resulting cloudy suspension wascooled to 0° C. in an ice bath. Pyrrole (385 mg, 5.75 mmol) in drytetrahydrofuran (2 ml) was added dropwise over a period of 10 min. Theice bath was removed and the solution was stirred at room temperatureuntil gas evolution ceased (1 5 minutes), whereupon5-bromothiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) previouslydissolved in tetrahydrofuran (4.0 ml) was added dropwise through a steelcannula. After stirring for 1 h at room temperature, the mixture wasfiltered through Celite. The filter pad was rinsed with tetrahydrofuran,and the filtrate was evaporated, which left a light brown solid that wasrecrystallized from methanol to produce the sulfonamide (821 mg, 74%yield) as a white powder.

B. 4-Ethylphenylboronic Acid

A solution of 1-bromo-4-ethyl benzene (2.0 g, 11 mmol) in dry ether (5ml) was added to magnesium turnings (311 mg, 13 mmol), which had beensuspended in dry ether, by dropwise addition. After addition wascomplete, the suspension was refluxed for a period of 1 5 min, by whichtime nearly all of the magnesium had reacted. The solution was thenadded to trimethyl borate (1.12 g, 11 mmol), previously dissolved inether (5 ml) at −₇₈° C., warmed to room temperature and stirred for 90min. The reaction was quenched by the addition of 10% aqueous HCl (2 ml)and the solution was extracted with ether. The combined ether extractwas extracted with 1 M NaOH (2×20 ml), the aqueous extracts wereacidified with dilute HCl to pH 2 and extracted with ether (2×25 ml).The resulting combined ether extract was washed once with water (10 ml),dried and evaporated to produce a white solid (676 mg, 38% yield), m.p.138-140° C.

C. N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole

N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole was prepared, in thesame manner as described in Example 13C, from 4-ethylphenylboronic acidand N-(5-bromothiophenesulfonyl)pyrrole. Purification by columnchromatography using 10% ethyl acetate/hexanes gave the pure sulfonamideas a tan solid in 81% yield.

D. 5-Chlorosulfonyl-2-(4-ethylphenyl)thiophene

A solution of N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole (100 mg,0.32 mmol) and 6 N sodium hydroxide (1 ml) in methanol (1.5 ml) wasrefluxed for approximately 6 h. Evaporation of solvents and drying invacuo resulted in an oil. Phosphorus oxychloride (258 ml, 2.52 mmol) andphosphorus pentachloride (1 31 mg, 0.63 mmol) were added to the oil andthe resulting brown suspension was heated at 50° C. for 3 h. Theresulting clear brown solution was carefully added to about 20 ml ofcrushed ice and then extracted with ethyl acetate (3×25 ml). Thecombined organic layers was washed with brine (2×5 ml), dried (MgSO₄)and evaporated to leave an oily residue. Flash chromatography oversilica gel using 2% ethyl acetate/hexanes yielded (53 mg, 59%) of thepure sulfonyl chloride as a pale yellow oil.

E.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described inExample 10. Reaction of 5-chlorosulfonyl-2-(4-ethylphenyl) thiophene(47.1 mg, 11.16 mmol) with 5-amino-4-bromo-3-methyl isoxazole (29 mg,0.1 6 mmol) yielded, after flash chromatography using 10% MeOH/CHCl₃, apale brown solid (46 mg, 66% yield), m.p. 172-175° C.

EXAMPLE 15

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-phenethylthiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenethylthiophene-2-sulfonamide wasprepared in the same manner as described in Example 1 0 from5-amino-4-bromo-3-methylisoxazole and 4-phenethyl-2-thiophenesulfonylchloride in 32% yield. This was purified by HPLC (5% CH₃CN to 100% CH₃CNover 30 min.) to give a gum.

EXAMPLE 16

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-carboxyphenylaminocarbonyl]thiophene-3-sulfonamide

Et₃N (2.27 ml. 16. mmol), ethyl 3-aminobenzoate (836 ml, 5.44 mmol) andphosphonitrilic chloride trimer (1.89 g, 5.44 mmol) were sequentiallyadded to a solution ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbonyl)thiophene-3-sulfonamide(Example 12) (1 g, 2.27 mmol) in dry THF (20 ml). The reaction wasstirred at room temperature for 1 hour and cooled. Water (5 ml) wasadded to quench the reaction. The resulting solution was concentrated ona rotavap. The residue was diluted with EtOAc and washed with 2 N HCl(2×150 ml). The organic layer was dried (MgSO₄). The solid was filteredoff and the filtrate was concentrated. The residue was treated with 1NNaOH (200 ml) and stirred at 0° C. for 15 minutes. The mixture was thenacidified with conc. HCl to pH ˜1. The resulting yellow precipitate wasfiltered off and recrystallized from CH₃CN/H₂O to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-carboxyphenyl)aminocarbonyl]thiophene-3-sulfonamide(1 53 mg., 11.6%) as a yellowish powder, m.p. 183-185° C.

EXAMPLE 17

N-(4-Bromo-5-methyl-3-isoxazolyl)-5-(4-methylphenylthiophene-2-sulfonamide

A. N-[5-(4-methylphenyl)thiophene-2-sulfonyl]pyrrole

N-[5-(4-methylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in thesame manner as described in Example 1 3C using 4-methyl-phenylboronicacid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by columnchromatography using 2% ethyl acetate/hexanes gaveN-[5-(4-methylphenyl)-thiophene-2-sulfonyl]pyrrole as a pale yellowsolid in 77% yield.

B. 2-chlorosulfonyl-5-(4-methylphenyl)thiophene

2-chlorosulfonyl-5-(4-methylphenyl)thiophene was prepared in the samemanner as described in Example 14D usingN-[5-(4-methylphenyl)thiophene-2-sulfonyl]pyrrole. Purification bycolumn chromatography using 2% ethyl acetate/hexanes gave2-chlorosulfonyl-5-(4-methylphenyi)thiophene as a pale yellow powder(61% yield).

C.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methylphenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methylphenyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 10. Reaction of2-chlorosulfonyl-5-(4-methylphenyl)thiophene (100 mg, 0.37 mmol) with5-amino-4-bromo-3-methylisoxazole (65 mg, 0.37 mmol) yielded, aftercolumn chromatography using 10% MeOH/CHCl₃, 96 mg final product as apale yellow solid, (63% yield, m.p. 175° C.).

EXAMPLE 18

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamide

A. 2-(benzyloxymethyl)thiophene

Sodium hydride (0.41 mg, 20 mmol) was added to a solution of 2-thiophenemethanol (2.0 g, 0.18 mmol) in THF (20 ml) at −40° C. The reaction wasstirred at −40° C. for 25 min., then neat benzylbromide (3.6 g, 20 mmol)was added by syringe. The solution was stirred at −40° C. for 0.5 hr,then at room temperature for 1 hr. The THF was evaporated off and theremaining residue was taken up in ether (˜50 ml). The organic solutionwas washed with water (1×10 ml), brine (1×10 ml) and dried over MgSO₄.Evaporation of solvents left an oil which was purified by columnchromatography using 1% etherhexanes to give 2.6 g of the thiophene as apale yellow oil (78% yield).

B. 2-chlorosulfonyl-5-(benzyloxymethyl)thiophene

2-chlorosulfonyl-5-(benzyloxymethyl)thiophene was prepared in the samemanner as described in Example 1 7A from 2-(benzyloxymethyl)thiophene(1.0 g, 5.25 mmol). Purification by column chromatography using 2.5%ethyl acetate/hexanes gave 520 mg of the pure thiophene as a brown oil(32% yield).

C.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamidewas prepared as described in Example 10 from2-chlorosulfonyl-5-(benzyloxymethyl)thiophene (520 mg, 1.72 mmol) and5-amino-4-bromo-3-methyl isoxazole (319 mg, 1.8 mmol). Purification bycolumn chromatography using 10% MeOH/CHCl₃) gave 238 mg of pureN-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamideas a brown semisolid (31% yield, m.p. 92° C).

EXAMPLE 19

N-(4-Bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl]thiophene-2-sulfonamide

A. 3-bromothiophene-2-sulfonyl chloride

Chlorosulfonic acid (20 ml, 300 mmol) was added to a solution of3-bromothiophene (8.15 g, 50 mmol) in methylene chloride (50 ml) at −78°C. over a 20 min. period. After the completion of addition, the coldbath was removed and stirring continued at ambient temperature for 1 hr.The reaction mixture was carefully added, dropwise, to crushed ice (100g). The mixture was extracted with methylene chloride (2×100 ml). Thecombined organic layers was dried over MgSO₄ and evaporated. The crudeproduct was purified by flash chromatography on silica gel using hexaneas the eluent resulting in 3-bromothiophene-2-sulfonyl chloride (4 g,30% yield) and 4-bromothiophene-2-sulfonyl chloride (200 mg, ≦1%).

B. N-(3-bromothiophene-2-sulfonyl)pyrrole

N-(3-bromothiophene-2-sulfonyl)pyrrole was prepared in the same manneras described in Example 14A by reacting3-bromothiophene-2-sulfonylchloride with pyrrole (for 16 hr.).N-(3-bromothiophene-2-sulfonyl)pyrrole was obtained in 54% yield.

C. N-{[3-(3,4-methylenedioxy) phenyl]thiophene-2-sulfonyl}pyrrole

N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole wasprepared in the same manner as described in Example 13C using3,4-methylenedioxyphenylboronic acid andN-(3-bromothiophene-2-sulfonyl)pyrrole. The crude product was purifiedby flash column chromatography on silica gel using 2% EtOAc in hexane asthe eluent resulting inN-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole in a 90%yield.

D. 2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl]thiophene

2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl]thiophene was prepared inthe same manner as described in Example 18B usingN-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole by basichydrolysis of the sulfonamide to the sodium sulfonate (100% yield)followed by conversion of the salt to the corresponding sulfonylchloride resulting in a 34% yield of the final product.

E.N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl]thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl]thiophene-2-sulfonamidewas prepared in the same manner as described in Example 9 by reaction of2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl]thiophene with5-amino-4-bromo-3-methylisoxazole resulting in a 60% yield, m.p.183-186° C.

EXAMPLE 20

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonamide

A. N-{2-[(3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonyl}pyrrole

Sodium hydride (100 mg, 5 mmol) was added to a stirred solution of3,4-methylenedioxyphenol (0.607 g, 4.5 mmol) in DMF (dry, 5 ml) at 0° C.under a nitrogen atmosphere with stirring. The reaction mixture waspermitted to attain room temp and stirring continued for 1 hr. Thereaction mixture was cooled to 0° C. andN-[(2-bromomethyl)thiophene-3-sulfonyl]pyrrole was added. Stirring wascontinued at ambient temperature for 16 hr. The reaction mixture wasdiluted with water (100 ml), extracted with ethyl acetate (2×50 ml) andwashed with 1 N NaOH (2×25 ml) to remove phenol derivative. The mixturewas dried over MgSO₄ and concentrated resulting inN-{2-[(3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonyl}pyrrole,which was recrystallized using hexane/EtOAc (1.0 g, 92% yield).

B.3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxy)phenoxymethyl]thiophene

3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxy)phenoxymethyl]thiophenewas prepared in the same manner as described in Example 15E usingN-({2-[(3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonyl}pyrrole byconducting a basic hydrolysis (using potassium hydroxide iniso-propanol) to the potassium sulfonate followed by conversion of thesalt to the corresponding sulfonyl chloride in an overall yield of 50%.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylenedioxy)-phenoxymethyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 9 by reaction of3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophenewith 5-amino-4-bromo-3-methylisoxazole, 47% yield, m.p. 152-154° C.

EXAMPLE 21

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonamide

A. Diethyl 2-{3-[(N-pyrrolyl)sulfonyl]thienylmethyl}phosphonate

N-[2-bromomethyl)thiophene-3-sulfonyl]pyrrole (0.915 g, 3 mmol) wassuspended in triethyl phosphite (5 ml) and was heated to 140° C. for 1hr. with stirring under nitrogen atmosphere. Excess triethyl phosphatewas removed under reduced pressure and the residue was dried undervacuum resulting in 0.9 g, 83% yield of diethyl2-{3-[(N-pyrrolyl)sulfonyl]thienylmethyl}phosphonate.

B. N-{2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonyl}pyrrole

Sodium hydride (200 mg, 60% dispersion) was added in two lots to thestirred solution of diethyl2-{3-[(N-pyrrolyl)sulfonyl]thienylmethyl)phosphonate (900 mg, 2.48 mmol)in dry THF (10 ml) at 0° C. The mixture was stirred at room temperaturefor 1 hr. then piperonal (600 mg) was added. Stirring was continued for12 hours. The mixture was diluted with water (100 ml) and extracted withmethylene chloride (2×50 ml). The combined organic layers was dried overMgSO₄, evaporated, and the residue was flash chromatographed on silicagel using 0.5% ethyl acetate in hexane to giveN-{2-[trans-(3,4-methylenedioxy)cinnamyl]thiophene-3-sulfonyl}pyrrole(750 mg, 84% yield).

C. 3-chlorosulfonyl-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene

3-chlorosulfonyl-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene wasprepared in the same manner as described in Example 1 5E fromN-{2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonyl}pyrrole bybasic hydrolysis (using isopropanol and potassium hydroxide) to thecorresponding potassium sulfonate (100%) followed by conversion of thesalt to the corresponding sulfonyl chloride in a 31% overall yield.

D.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 9 by reaction of3-chlorosulfonyl-2-[trans-3,4-(methylenedioxy)-cinnamyl]thiophene with5-amino-4-bromo-3-methylisoxazole. The crude product was purified byHPLC resulting in a 33% yield, m.p. 147-149° C.

EXAMPLE 22

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamide

A. N-{2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonyl}pyrrole

An ethyl acetate (1 5 ml) solution ofN-(2-[trans-3,4-(methylenedioxy)-cinnamyl]thiophene-3-sulfonyl)pyrrole(Example 21B, 0.6 g, 1.67 mmol) was subjected to catalytic hydrogenationusing 10% Pd-C (100 mg) at 55 psi for 14 hr. The catalyst was filteredand the filtrate concentrated to resulting inN-{2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonyl}pyrrole (0.55g, 91% yield).

B. 3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene

3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene was preparedin the same manner as described in the Example 1 5E usingN-{2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonyl}pyrrole byconducting basic hydrolysis (iso-propanol and potassium hydroxide) ofthe sulfonamide to the potassium salt of sulfonic acid (93%) followed byconversion of the salt to the corresponding sulfonyl chloride in a 42%yield.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]-thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]-thiophene-3-sulfonamidewas prepared in the same manner as described in Example 10. By reacting3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]-thiophene with5-amino-4-bromo-3-methylisoxazole and purifying the crude product byHPLC,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-phenethyl]thiophene-3-sulfonamidewas obtained in a 30% yield, m.p. 180° (dec.).

EXAMPLE 23

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)(cinnamyl)]thiophene-3-sulfonamide

A. N-[2-(4-methyl-trans-styryl)-3-sulfonyl}pyrrole

N-[2-(4-methyl-trans-styryl)-3-sulfonyl}pyrrole was prepared in the samemanner as described in Example 21 B usingdiethyl{3-[(N-pyrrolylsulfonyl)thien-2-[yl]methyphosphonate and4-methylbenzaldehyde in 30% yield.

B. 2-(4-methyl-trans-styryl)thiophene-3-sulfonyl chloride

2-(4-methyl-trans-styryl)thiophene-3-sulfonyl chloride was prepared inthe same manner as described in Example 15E fromN-[2-(4-methyl-trans-styryl)-3-sulfonyl}pyrrole by basic hydrolysis(using ethanol and sodium hydroxide) to the corresponding sodiumsulfonate followed by conversion to the corresponding sulfonyl chloridein 13% yield.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methyl-trans-styryl)thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methyl-trans-styryl)thiophene-3-sulfonamidewas prepared in the same manner as described in Example 10 by reactionof 2-(4-methyl-trans-styryl)thiophene-3-sulfonyl chloride with5-amino-4-bromo-3-methylisoxazole. The crude product was purified byHPLC followed by crystallization resulting in a 34% yield, m.p. 101-105°C.

EXAMPLE 24

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thiophene-3-sulfonamide

A. N-{2-[(4-methyl)phenethyl]thiophene-3-sulfonyl}pyrrole

N-{2-[(4-methyl)phenethyl]thiophene-3-sulfonyl}pyrrole was prepared asdescribed in Example 22A by the catalytic hydrogenation ofN-[2-(4-methyl-trans-styryl)-3-sulfonyl)pyrrole in 80% yield.

B. 2-[(4-methyl)phenethyl]thiophene-3-sulfonylchloride

2-[(4-methyl)phenethyl]thiophene-3-sulfonylchloride was prepared, asdescribed in Example 15E, usingN-{2-[(4-methyl)phenethyl]thiophene-3-sulfonyl}pyrrole by basichydrolysis (KOH/ethanol) of the sulfonamide to this potassium saltfollowed by conversion of salt to the corresponding sulfonyl chloride in51% yield.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thiophene-3-sulfonamidewas prepared, as described in Example 10, using2-[(4-methyl)-phenethyl]thiophene-3-sulfonylchloride and5-amino-4-bromo-3-methylisoxazole in 52% yield.

EXAMPLE 25

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfonamide

A. N-{2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl}pyrrole

N-{2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl}pyrrole was prepared,as described in Example 20A, by reactingN-[2-bromomethyl)thiophene-3-sulfonyl]pyrrole with 4-methylphenol, in81% yield.

B. 2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl chloride

2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl chloride was prepared,as described in Example 1 5E, usingN-{2-[(4-methylphenoxymethyl]thiophene-3-sulfonyl}pyrrole by basichydrolysis (NaOH/EtOH) followed by conversion to the correspondingsulfonyl chloride, in 46% yield.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfonamidewas prepared, as described in Example 10, by reacting3-chlorosulfonyl-2-[(4-methylphenoxy)methyl]thiophene with5-amino-4-bromo-3-methylisoxazole, resulting in a 64% yield, m.p.128-130° C.

EXAMPLE 26

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylaminocarbonyl-3-thiophenesulfonamide

A. (3,4-methylenedioxy)-6-methylaniline

To a solution of (3,4-methylenedioxy)toluene (5 ml) in acetic acid (20ml) cooled with a cold water bath was added, dropwise, nitric acid (70%,5 ml). The mixture was stirred for 45 min. To work up, water (100 ml)was added and the resulting yellow precipitate was filtered and washedwith water until the aqueous filtrate was colorless. The yellow solidwas dissolved in EtOAc (250 ml) and dried (MgSO₄), and the solid wasfiltered off. The filtrate was subjected to catalytic hydrogenation (10% Pd/C, 1 atm) for 1 2 hours. The reaction mixture was then filteredoff the catalyst and the filtrate was concentrated on a rotavap to give(3,4-methylenedioxy)-6-methylaniline as a brownish grey solid (5.49 g,87% yield).

B.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 3 using(3,4-methylenedioxy)-6-methylaniline. The crude product was purified bypreparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylaminocarbonyl-3-thiophenesulfonamideas a yellow solid (45% yield, m.p. 60-62° C.).

EXAMPLE 27

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamide

A. Methyl 3-amino-2,4,6-trimethylbenzoate

Methyl 3-amino-2,4,6-trimethylbenzoate was synthesized in the samemanner as (3,4-methylenedioxy)-6-methylaniline (see Example 26).

B.N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 3 except that DMF wasused instead of THF and the reaction was heated at 80° C. for 5 hours.The crude product was purified via preparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamideas an off-white powder (48 mg, 1% yield, m.p. 66-70° C.).

EXAMPLE 28

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 5 using2,4,6-trimethylbenzyl chloride andN-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N′-methoxy)aminocarbonyl-3-thiophenesulfonamide.The crude product was purified by flash column chromatography (eluent 1%methanol in CH₂Cl₂) to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamideas a solid (31% yield, m.p. 42-46° C.).

EXAMPLE 29

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 3. The crude product waspurified via preparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamideas a yellowish-brownish powder (410 mg, 30% yield, m.p. 45-48° C.).

EXAMPLE 30

N-(3,4-dimethyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamidewas synthesized by the same method as described for Example 5 using2,4-dimethylbenzyl chloride andN-(3,4-dimethyl-5-isoxazolyl)-2-(N-methyl-N′-methoxy)aminocarbonyl-3-thiophenesulfonamide.The crude product was purified by flash column chromatography (eluent 1%methanol in CH₂Cl₂) and further by preparative HPLC to giveN-(3,4-dimethyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamideas a semi-solid (34% yield).

EXAMPLE 31

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-di methyl)phenylacetyl-3-thiophenesulfonamide was synthesized in the same manneras for Example 5 using 2,4-dimethylbenzyl chloride andN-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N′-methoxy)aminocarbonyl-3-thiophenesulfonamide.The crude product was purified by flash column chromatography (eluent 1%methanol in CH₂Cl₂) to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamideas a solid (52% yield, m.p. 48-54° C.).

EXAMPLE 32

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 5 using2,4-dimethylbenzyl chloride andN-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-methyl-N′-methoxy)aminocarbonyl-3-thiophenesulfonamide.The crude product was purified by flash column chromatography (eluent 1%methanol in CH₂Cl₂) and further by preparative HPLC to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamideas a solid (28% yield, m.p. 58-63° C.).

EXAMPLE 33

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylacetyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 5 using3,5-dimethylbenzyl bromide andN-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N′-methoxy)aminocarbonyl-3-thiophenesulfonamide.The crude product was purified by flash column chromatography (eluent 2%methanol in CH₂Cl₂) to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylacetyl-3-thiophenesulfonamideas a solid (57% yield, m.p. 45-50° C.).

EXAMPLE 34

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 5 using2,5-dimethylbenzyl chloride andN-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N′-methoxy)aminocarbonyl-3-thiophenesulfonamide.The crude product was purified by flash column chromatography (eluent 2%methanol in CH₂Cl₂) to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl-3-thiophenesulfonamideas a solid (33% yield, m.p. 72-76° C.).

EXAMPLE 35

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamide

A. 2-(3,4-methylenedioxy)phenyl-1-ethanol

To a solution of 2-(3,4-methylenedioxy)phenylacetic acid (5 g, 25.75mmol) in anhydrous THF (20 ml) at 0° C. was added BH₃THF (40 ml, 1.0 Min THF). The mixture was stirred at room temperature for 1 h. To workup, THF was evaporated on a rotavap. The residue was treated with water(100 ml) Acidified and extracted with ether (2×100 ml). Removal of thesolvent under reduced pressure gave2-(3,4-methylenedioxy)phenyl-1-ethanol as an oil (4.7 g, 98% yield).

B. 1-acetoxy-2-[(3,4-methylenedioxy)phenyl]ethane

To a stirred solution of 2-(3,4-methylenedioxy)phenyl-1-ethanol (1.68 g,10 mmol) in dry pyridine was added acetic anhydride and the resultantreaction mixture was stirred at 80° C. for 1h. The reaction mixture waspoured into ice-water and was extracted with ether (2×75 ml). Thecombined ether extract was washed with water (2×50 ml), 5% HCl (2×50 ml)and then with 5% NaHCO₃ (2×50 ml). The organic layer was dried overmagnesium sulfate and the solvent was removed under reduced pressure togive 1-acetoxy-2-[(3,4-methylenedioxy)phenyl]ethane as a solid (1.7 g,81% yield).

C. 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane

To a stirred solution of 1-acetoxy-2-[(3,4-methylenedioxy)-phenyl]ethane(1.7 g, 8.09 mmol) in acetic acid (10 ml) was added, dropwise,concentrated HNO₃ (4.5 ml). This was stirred at room temperature for 30min. The reaction mixture was poured into water (100 ml). Theprecipitated solid was filtered, washed with water and dried under highvacuum to get 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane(1.8 g, 88% yield).

D. 1-acetoxy-2-[(3,4-methylenedioxy)-6-aminophenyl]ethane

The solution of 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane(0.8 g, 3.13 mmol) in ethyl acetate (25 ml) was subjected to catalytichydrogenation using 10% palladium on carbon (100 mg) at 50 psi for 30min. The catalyst was filtered and the solvent was removed under reducedpressure to give 1-acetoxy-2-[(3,4-methylenedioxy)-6-aminophenyl]ethaneas a solid (0.69 g, 98% yield).

E.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 16. The crude product waspurified by preparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamideas a dull yellow powder (12% yield, m.p. 78-82° C.).

EXAMPLE 36

Other compounds that have been prepared by the above methods or routinemodifications thereof, include, but are not limited to:N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxyphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4-methylphenoxy)methyl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-trans-styryl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenethyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenyl)acetyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)acetyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenethyl)-5-(4-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylbenzyl)-5-(4-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-trans-styryl)-5-(4-tolyl)thiophene-2-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzylthiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(5-methyl-3-isoxazolyl)aminocarbonyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-hydroxyl-6-pyridazinyl)aminocarbonyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-{[3,4-(methylenedioxy)phenoxylmethyl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)(cinnamyl)]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)-phenethyl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)-trans-styryl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thiophene-3-sulfonamide,N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetylphenyl)thiophene-3-sulfonamide,N-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-hydroxy-4-methylphenyl)aminocarbonyl]thiophene-3-sulfonamideand others, including those set forth in TABLE 1 that are notspecifically exemplified herein.

For example,N-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-methyl-4,5-(methylenedioxy)cinnamyl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-(hydroxymethyl)-4,5-(methylenedioxy)cinnamyl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-{2-[(tetrahydro-4H-pyran-2-ylxoy)methyl]-4,5-(methylenedioxy)cinnamyl}thiophene-2-sulfonamideandN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4-dimethylcinnamyl)thiophene-2-sulfonamidehave been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)-trans-styryl]thiophene-2-sulfonamide.N-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-methyl-4,5-(methylenedioxy)phenethyl]thiophene-2-sulfonamideandN-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethylphenethyl)thiophene-3-sulfonamidehave been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thiophene-3-sulfonamide(see, Example 24).N-(4-bromo-3-methyl-5-isoxazolyl)-3-{[2-propyl-4,5-(methylenedioxy)phenoxy]methyl}thiophene-2-sulfonamidehas been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4-methylphenoxy)methyl]thiophene-2-sulfonamideandN-(4-bromo-3-methyl-5-isoxazolyl)-3-{3,4-(methylenedioxy)phenoxymethyl}thiophene-2-sulfonamide.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenethyl]-thiophene-3-sulfonamidehas been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenethyl]thiophene-3-sulfonamide.Compounds, such asN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-methoxyphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-methoxyphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methoxyphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-ethylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-propylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-propylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-butylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4-dimethylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-isobutylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-pentylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methyl-4-propylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-butyl-2-methylphenyl)thiophene-2-sulfonamideandN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-pentyl-2-methylphenyl)thiophene-2-sulfonamidehave been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(3,4-methylenedioxy)phenyl]thiophene-2-sulfonamide(see, Example 125 of International Patent Application Publication No. WO96/31492).

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenethyl]thiophene-3-sulfonamidehas been prepared in the same manner asN-(4-Bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamide(Example 22).N-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)cinnamyl]thiophene-3-sulfonamidehas been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)(cinnamyl)]thiophene-3-sulfonamide (Example 23).

N-(4-bromo-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-phenoxy]methyl}thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)methyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-{[4,5-(methylenedioxy)-2-propylphenoxylmethyl}thiophene-3-sulfonamidehave been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfonamide(Example 25).

Any corresponding N-(4-halo-3-methyl-5-isoxazolyl),N-(4-halo-5-methyl-3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyl),N-(4-halo-5-methyl-3-isoxazolyl), N-(4-halo-3-methyl-5-isoxazolyl),N-(4,5-dimethyl-3-isoxazolyl) derivative of any of these compounds orany compound disclosed herein may also be prepared and used as describedherein. The pharmaceutically acceptable derivatives, including thesalts, particularly sodium salts are intended for formulation asdescribed herein.

EXAMPLE 37

Other compounds that can be prepared by the above methods or routinemodifications thereof, include, but are not limited to:

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-acetylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methoxycarbonylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-carboxylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methanesulfonylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimethoxy-6-(cyanomethyl)phenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimethoxy-6-(2-hydroxyethyl)phenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-acetylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-methoxycarbonylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-carboxylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-methanesulfonylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-cyanophenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-cyanomethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-(2-hydroxyethyl)phenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-acetyl-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxycarbonyl-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-carboxyl-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesulIfonyl-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyano-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(cyanomethyl)-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-hydroxyethyl)-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-cyano-6-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-cyanophenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-acetyl-6-methylphenylaminocarbonyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-acetylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxyl-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(2-hydroxyethyl)-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(carboxylmethyl)-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-cyano-2,6-dimethylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-carboxyl-2,6-dimethylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(hydroxymethyl)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(2-hydroxyethyl)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(cyanomethyl)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(carboxylmethyl)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methanesulfonyl-2,6-dimethylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-acetylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methoxycarbonylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-carboxylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methanesulfonylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimethoxy-6-(cyanomethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimethoxy-6-(2-hydroxyethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-acetylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-methoxycarbonylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-carboxylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy-2-methoxy-6-methanesulfonyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-(cyano)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-(cyanomethylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-(2-hydroxyethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2,6-dimethylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-acetyl-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxycarbonyl-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-carboxyl-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesulfonyl-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyano-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(cyanomethyl)-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-hydroxyethyl)-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-cyano-6-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-cyanophenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-acetyl-6-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-acetylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxyl-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(cyanomethyl)-2,4,6-trimethylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(2-hydroxyethyl)-2,4,6-trimethylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(carboxylmethyl)-2,4,6-trimethylphenylacetyljthiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-cyano-2,6-dimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-carboxyl-2,6-dimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-hydroxymethyl-2,6-dimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(2-hydroxyethyl)-2,6-(dimethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-cyanomethyl-2,6-(dimethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(carboxylmethyl)-2,6-dimethylphenylacetyl]thiophene-3-sulfonamide,and

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methanesulfonyl-2,6-dimethylphenylacetyl)thiophene-3-sulfonamide.The pharmaceutically acceptable derivatives, including the salts,particularly sodium salts are intended for formulation as describedherein.

EXAMPLE 38

Other compounds, having activity generally at IC₅₀ concentrations of 10μM or substantially less for ET_(A) or ET_(B) receptors, in which Ar²contains a heterocyclic ring, such as thienyl-, furyl- andpyrrole-sulfonamides of interest herein, can be or have been prepared(see, e.g., TABLE 1) by methods analogous to those set forth in theabove Examples. Such compounds include, but are not limited to thefollowing compounds:N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxyl-1-methylindole-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-oxacyclohexyl)oxycarbonyl]thiophene-3-sulfonamide,2-[3,4-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-{2-[3,4-(methylenedioxy)phenyl]acetyl}thiophene-3-sulfonamideoxime, N-(4-chloro-3-methyl-5-isoxazolyl)-2-phenylbenzo[b]thiophenesulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-tolyl)aminocarbonyl]-1-methylindole-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxyphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-1-[3,4-(methylenedioxy)benzyl]indole-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxyphenyl)acetyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-6-methoxy-2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4-methylphenoxy)-methyl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-trans-styryl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenethyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenyl)acetyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)acetyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-hydroxy-1-[3,4-(methylenedioxy)-benzyl]ethyl}thiophene-3-sulfonamide,N-4-(bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenethyl)(4-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylbenzyl)-5-(4-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-trans-styryl)-5-(4-tolyl)thiophene-2-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[ββ-(ethylenedioxy)3,4-(methylenedioxy)-phenethyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[β-(dimethylamino)-3,4-(methylenedioxy)phenethylthiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-{α-hydroxy-3,4-(methylenedioxy)phenylacetyl}-thiophene-3-sulfonamide;N-(4-chloro-5-methyl-3-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-styrylthiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-styrylthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzoylamino)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(phenyl)-methylaminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(hydroxymethyl)furan-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(carbomethoxy)furan-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethylfuran-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(diisopropylaminocarbonyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(diethylaminocarbonyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-styrylfuran-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-styrylthiophene-2-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-5-(dimethylamino)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-7-methoxybenzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-7-phenoxybenzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-5-methoxy-benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-5-isobutylaminobenzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-5-benzyl-aminobenzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxy]benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxy]-5-dimethylamino-benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenyl]acetyl-5-dimethylaminobenzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzylcarbonyl]-N-methylindole-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxycarbonyl]indole-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxycarbonyl]-N-methylindole-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxycarbonyl]indole-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-N-methylindole-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]indole-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyloxycarbonyl]-7-(N,N-di-methylamino)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-7-(N,N-dimethylamino)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzoyl]-7-(N,N-dimethyl)amino)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-7-(N,N-dimethylamino)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-7-(methoxycarbonyl)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-7-(methoxy)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-7-(methoxy)benzo[b]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methylphenethyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(trans-4-methylcinnamyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenethyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-methylphenethyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methylphenethyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(trans-4-methylcinnamyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(trans-3-methylcinnamyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(trans-2-methylcinnamyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4-methylphenoxy)methyl]thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenethyl]thiophene-2-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{(3,4-(dimethoxy)phenyl]acetyl)}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,5-dimethoxyphenyl)acetyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4,5-trimethoxyphenyl)acetyl]-thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzylsulfonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzylsulfinyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzylsulfenyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-(dimethylamino)-2-[3,4-(methylenedioxy)phenyl}ethylthiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-methylamino)-2-13,4-(methylenedioxy)phenyl]ethyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-(methoxylimino)-2-[3,4-(methylenedioxy)phenyl]ethyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-(carboxyl)-2-[3,4-(methylenedioxy)phenyl]ethyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2-(carboxyl)-1-[3,4-(methylenedioxy)benzyl]vinyl)thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{3-[3,4-(methylenedioxy)phenyl]-1,2,4-oxadiazol-5-lyl}thiophene-3-sulfonamide;andN-(4-chloro-3-methyl-5-isoxazolyl-2-{3-[3,4-(methylenedioxy)benzyl]-1,2,4-oxadiazol-5-lyl}thiophene-3-sulfonamide.

Additional compounds include, but are not limited to:N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(methanesulfonyl)-4,5-(methylenedioxy)phenyl]amino-carbonyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-carboxylphenyl]aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4,5-(methylenedioxy)-2-(methoxycarbonyl]phenyl}aminocarbonyl}thiophene-3-sulfonamide;N-(4-chioro-3-methyl-5-isoxazolyl)-2-{[2-cyano-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4,5-(methylenedioxy)-2-hydroxymethyl)phenyl]aminocarbonylthiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-acetyl-4-methylphenyl]aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(methanesulfonyl)-4-methylphenyl]aminocarbonyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-carboxyl-4-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methoxycarbonyl-4-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-3-isoxazolyl)-2-[(2-cyano-4-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(hydroxymethyl)-4-methylphenyl]aminocarbonyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-dimethoxy-6-acetylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(methanesulfonyl)-4,5-dimethoxyphenyl]aminocarbonyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-di-methoxy-2-carboxylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-methoxycarboxyl)phenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-cyano(4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4,5-dimethoxy-2-hydroxymethyl)phenylaminocarbonylthiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-acetyl-4,5-(methylenedioxy)phenyl]acetyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(methanesulfonyl)-4,5-(methylenedioxy)phenyl]-acetyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[carboxyl4,5-(methylenedioxy)-2-phenylacetylthiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4,5-(methylenedioxy)-2-methoxycarbonylphenyl]-acetylthiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-cyano[4,5-(methylenedioxy)-phenyl]acetyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2-hydroxymethyl[4,5-(methylenedioxy)-phenyl]-acetyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-dimethoxy)phenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,3-dimethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-di-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,5-dimethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,6-dimethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-dimethylphenyl)-aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,5-dimethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylaminocarbonylthiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methoxy-6-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenyl)aminocarbonyl]-thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methylphenyl)aminocarbonyl]-thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-ethyl(4-methoxy-)phenyl)aminocarbonyl)thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-isopropyl-4-methoxy-phenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-propyl-4-methoxy-phenyl)aminocarbonyl]-thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-biphenylaminocarbonyl]-thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)acetyl]-thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-ethylphenyl)acetyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methoxyphenyl]acetyl]thiophene-3-sulfonamide.

The pharmaceutically acceptable derivatives, including the salts,particularly sodium salts are intended for formulation as describedherein.

EXAMPLE 39

N-(2-Acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide

A. 2′-Amino-3′,5′-dimethylacetophenone

To a solution of BCl₃ in dichloromethane (1.0 M, 25 mL) at 0° C. wasslowly added 2,4-dimethylaniline (3.03 9, 25 mmol) in 1,2-dichloroethane(25 mL). Acetonitrile (25 mL) was then added dropwise at 0° C. Themixture was then heated with a bath temperature of 100° C. for 2 dayswith a slow and steady flow of nitrogen to remove the low boilingdichloromethane. The reaction was cooled to 0° C. and quenched with 2 NHCl (˜25 mL) and the mixture was heated at 80° C. until a homogenoussolution formed (˜20 min). This was allowed to cool to room temperatureand the two layers were separated. The aqueous layer was basified withsodium bicarbonate until no more gas evolution was seen and muchprecipitate formed. The mixture was then extracted with chloroform (˜30mL) and the organic layers were combined and concentrated. The residuewas dissolved in ethyl acetate (50 mL) and washed with 1 N NaOH (40 mL).The organic layer was then dried (MgSO₄), the solids were filtered, andthe filtrate was concentrated. The oily residue was dissolved in ethylether (˜5 mL) and let stand at room temperature for 24 h. The resultingyellow precipitate was filtered to give2′-amino-3′,5′-dimethylacetophenone (1.3 g, 30%).

B.N-(2-Acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide

To a solution of 2′-amino-3′,5′-dimethylacetophenone (1.9 g, 11.66 mmol)in dichloromethane (20 mL) at room temperature was addedN-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarbonylchloride (Example 51) (1 g, 2.86 mmol). The mixture was stirred for 10 hduring which much yellow precipitate formed. The reaction was thenconcentrated and the residue was diluted with ethyl acetate (50 mL) andwashed with 1 N HCl (50 mL). The organic layer was concentrated and theresidue was dissolved in methanol (30 mL) followed by the addition ofconcentrated HCl (15 mL). The mixture was then heated under reflux for 2h before it was cooled to room temperature, diluted with ethyl acetate(200 mL) and washed with water (2×200 mL). The organic layer wasseparated, dried (MgSO₄), the solids filtered and the filtrateconcentrated. The residue was then purified by reverse phase HPLC togiveN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide(580 mg, 43%).

EXAMPLE 40

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-2-thiophenecarboxamide

A. 2′-Amino-3′,5′-dimethylpropiophenone

2′-Amino-3′,5′-dimethylpropiophenone was synthesized in the same fashionas for 2′-amino-3′,5′-dimethylacetophenone (Example 39) except thatpropionitrile was used instead of acetonitrile.

B.3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-2-thiophenecarboxamide

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-2-thiophenecarboxamidewas synthesized in the same fashion as forN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide(Example 39) except that 2′-amino-3′,5′-dimethylpropiophenone was usedinstead of 2-amino-3′,5′-dimethylacetophenone.

EXAMPLE 41

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-2-thiophenecarboxamide

A. 2′-Amino-3′,5′-dimethyl-2-methylpropiophenone

2′-Amino-3′,5′-dimethyl-2-methylpropriophenone was synthesized in thesame fashion as for 2′-amino-3′,5′-dimethylacetophenone (Example 39)except that isobutyronitrile was used instead of acetonitrile.

B.3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-2-thiophenecarboxamide

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-2-thiophenecarboxamidewas synthesized in the same fashion as forN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide(Example 39) except that 2′-amino-3′,5′-dimethyl-2-methylpropiophenonewas used instead of 2′-amino-3′,5′-dimethylacetophenone.

EXAMPLE 42

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexyicarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide

A. Cyclohexyl 2-amino-3,5-dimethylphenyl Ketone

Cyclohexyl 2-amino-3,5-dimethylacetophenone was synthesized in the samefashion as for 2′-amino-3′,5′-dimethylacetophenone (Example 39) exceptthat cyclohexyl cyanide was used instead of acetonitrile.

B.3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamidewas synthesized in the same fashion as forN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide(Example 39) except that cyclohexyl 2-amino-3,5-dimethylphenyl ketonewas used instead of 2′-amino-3′,5′-dimethylacetophenone.

EXAMPLE 43

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide

A. Cyclopropyl 2-amino-3,5-dimethylphenyl Ketone

Cyclopropyl 2-amino-3,5-dimethylphenyl ketone was synthesized in thesame fashion as for 2′-amino-3′,5′-dimethylacetophenone (Example 39)except that cyclopropyl cyanide was used instead of acetonitrile.

B.3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamidewas synthesized in the same fashion as forN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide(Example 39) except that cyclopropyl 2-amino-3,5-dimethylphenyl ketonewas used instead of 2′-amino-3′,5′-dimethylacetophenone.

EXAMPLE 44

N-(2-Benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide

A. 2-Amino-3,5-dimethylphenyl Phenyl Ketone

2-Amino-3,5-dimethylphenyl phenyl ketone was synthesized in the samefashion as for 2′-amino-3′,5′-dimethylacetophenone (Example 39) exceptthat benzonitrile was used instead of acetonitrile.

B.N-(2-Benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide

N-(2-Benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamidewas synthesized in the same fashion as forN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide(Example 39) except that 2-amino-3,5-dimethylphenyl phenyl ketone wasused instead of 2′-amino-3′,5′-dimethylacetophenone.

EXAMPLE 45

N-(2-Acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide

A.N-(4-Chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2-thiophenecarboxylicAcid

To a solution ofN-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-2-thiophenecarboxylicacid (6 g, 18.60 mmol) in anhydrous tetrahydrofuran (240 mL) at −78° C.and under nitrogen was added nBuLi (2.5 M in hexane, 30 mL, 74.4 mmol).The mixture was stirred at this temperature for 2 h before the additionof iodomethane (6.6 g, 74.4 mmol). The mixture was then poured intocrushed ice and then allowed to warm to room temperature. Afteracidification with concentrated HCl to pH ˜1, the mixture was extractedwith ethyl acetate (2×200 mL). The organic layers were combined, dried(MgSO₄), the solids were filtered and the filtrate was concentrated togiveN-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2-thiophenecarboxylicacid and the starting material in about a 2:1 ratio (8.5 g combinedweight).

B.N-(4-Chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2-thiophenecarboxylicAcid

To a solution of the product mixture of Example 45A (8.5 g) in THF (150mL) were sequentially added diisopropylethylamine (9.62 9, 74.4 mmol)and bromomethyl methyl ether (90%, 7.75 g, 55.80 mmol). The mixture wasstirred for 10 h before the addition of morpholine (4.6 g, 55.80 mmol)to scavenge the excess bromomethyl methyl ether. The reaction wasstirred for another 30 min before it was diluted with ethyl acetate (150mL) and washed with 1 N HCl (200 mL). The organic layer was dried(MgSO₄), the solids were filtered and the filtrate was concentrated. Theresidue was chromatographed (10% ethyl acetate in hexanes) to givemethoxymethylN-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-5-methyl-2-thiophenecarboxylate.The carboxylate was then hydrolyzed with 1 N NaOH to give thecorresponding carboxylic acid (3.5 g).

C.N-(4-Chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5-methyl-2-thiophenecarboxylicAcid Chloride

N-(4-Chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5-methyl-2-thiophenecarboxylicacid chloride was synthesized in the same fashion as forN-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarbonylchloride (Example 51) except thatN-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5-methyl-2-thiophenecarboxylicacid was used instead ofN-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarboxylicacid.

D.N-(2-Acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide

N-(2-Acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamidewas synthesized in the same fashion as forN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide(Example 39) except thatN-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-5-methyl-2-thiophenecarboxylicacid chloride was used instead ofN-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarboxylicacid chloride.

EXAMPLE 46

3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide

To a solution ofN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide(Example 39) (50 mg, 0.11 mmol) in 2 N NaOH (40 mL) and methanol (4 mL)was added hydroxylamine hydrochloride (4 9, 57.6 mmol). The mixture washeated at 60° C. for 3 h before it was cooled to 0° C. and acidifiedwith concentrated HCl to pH 1-2. The resulting white precipitate wasfiltered, washed with dilute acid and dried by lyophilization to give3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide(45 mg, 87%).

EXAMPLE 47

3-(((3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-2,4,6-trimethylphenylmethyl carbonate

To a solution ofN²-(4-chloro-3-methyl-5-isoxazolyl)-N-(3-hydroxy-2,4,6-trimethylphenyl)-3-sulfamoyl-2-thiophenecarboxamide(Example 52) (238 mg, 0.524 mmol) in anhydrous DMF at 0° C. was addedpotassium tert-butoxide (177 mg, 1.57 mmol). After the mixture wasstirred for 30 min at this temperature, methyl chloroformate (99.2 mg,1.05 mmol) was added. The reaction was poured into iced diluted acid andthe resulting precipitate was collected and purified by HPLC to give3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-2,4,6-trimethylphenylmethyl carbonate (186 mg, 70%).

EXAMPLE 48

3-(((3-(((4-Chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-2,4,6-trimethylphenylcarbamate

To a solution ofN²-(4-chloro-3-methyl-5-isoxazolyl)-N-(3-hydroxy-2,4,6-trimethylphenyl)-3-sulfamoyl-2-thiophenecarboxamide(Example 52) (500 mg, 1.05 mmol) in anhydrous DMF at 0° C. was addedpotassium tert-butoxide (295 mg, 2.61 mmol). After the mixture wasstirred for 10 min at this temperature, p-nitrophenyl chloroformate (317mg, 1.57 mmol) was added. After about 1 min stirring, the mixture wastreated with ammonium hydroxide (8 mL) and stirring was continued atroom temperature for 2 h. The reaction was poured into iced dilute acidand the resulting precipitate was collected and purified by HPLC to give3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-2,4,6-trimethylphenylcarbamate (213 mg, 42%).

EXAMPLE 49

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamide

A.N-(4-Chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-2-thiophenecarbonitrile

A solution ofN-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-2-thiophenecarboxamide (5g, 15.6 mmol) in POCl₃ (50 mL) was heated at 60° C. for 3 h. Thereaction was cooled to room temperature and poured to crushed ice (˜250g), and the icy mixture was shaken, stirred until all the ice melted(˜2h). The mixture was extracted with ethyl acetate and the organiclayer was dried (MgSO₄), the solids were filtered and the filtrate wasconcentrated and dried under vacuum to giveN-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-2-thiophenecarbonitrile(4.8 g˜100%).

B. 3-Methoxy-2,4,6-trimethylbenzyl Chloride

3-Methoxy-2,4,6-trimethylbenzyl chloride was synthesized in the samefashion as for 5-chloromethyl-6-methylbenzo[d][1,3]dioxole (Example 7)except that 1-methoxy-2,4,6-trimethylbenzene was used instead of5-methylbenzo[d][1,3]dioxole.

C.N-(4-Chloro-3-methyl-5-isoxazoly)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamide

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamidewas synthesized in the same fashion as for4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazole(Example 7) except thatN-(4-chloro-3-methyl-5-isoxazolyl)-3-sulfamoyl-2-thiophenecarbonitrile(Example 49A) was used instead ofN²-methoxy-N²-methyl-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide.

EXAMPLE 50

N-(4-Chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamide

To a solution ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamide(Example 49) (50 mg, 0.107 mmol) in dichloromethane (20 mL) at 0° C. wasadded BBr₃ (1 M in dichloromethane, 3 mL, 3.0 mmol). The resultingmixture was stirred at 0° C. for 1 h and at room temperature for 8 hbefore it was poured into crushed ice (˜100 g). The aqueous mixture wasstirred until all ice melted and extracted with dichloromethane (2×100mL). The organic layers were combined and concentrated, and the residuewas purified by HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamide(47 mg, 85%).

EXAMPLE 51

N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarbonylchloride

A. 5-Amino-4-chloro-3-methylisoxazole

To a solution of 5-amino-3-methylisoxazole (9.8 g, 100 mmol) inmethylene chloride (200 mL) was added N-chlorosuccinimide (14.7 g, 110mmol) at 0° C. over the period of 20 min. The reaction mixture wasstirred for 2h at RT. To work up the reaction mixture was concentratedand partitioned between 1 N NaOH (1 50 mL)/ethyl acetate (400 mL). Theorganic layer was washed with 1 N NaOH, water, brine, dried over MgSO₄then concentrated to a brown solid. For purification the product wasreprecipitated from chloroform/hexane then recrystallized from ethylacetate/hexane to give 5-amino-4-chloro-3-methylisoxazole as a brownishsolid (5.5 g, 41%).

B.2-Carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)]thiophenesulfonamide

To a slurry of 60% mineral oil suspension of NaH (8.5 g, 0.21 mol) inTHF (100 mL) at −20° C. was added a solution of5-amino-4-chloro-3-methylisoxazole (1 2.4 g, 92.4 mmol) in anhydrous THF(65 mL) under nitrogen over a period of 20 min. After 10 min stirringwas added a solution of 2-carbomethoxy-3-thiophenesulfonyl chloride(22.2 g, 92.4 mmol) in THF (65 mL) at −20° C. over 15 min. The reactionmixture was stirred for 10 min then quenched with H₂O (5 mL) at the sametemperature. To work up the reaction mixture was poured into 4 N HCl andthe product was extracted with ethyl acetate. The combined organics werewashed with water then the compound was extracted with half-saturatedNaHCO₃. The combined basic solutions were decolorized with activatedcharcoal, cooled to 0° C. and acidified with 4 N HCl. The product wasisolated by filtration, washed with water, dried to give2-carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)]thiophenesulfonamideas a white powder (23.4 g, 75%).

C.2-Carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N-methoxymethyl]thiophenesulfonamide

To a solution of2-carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)]thiophenesulfonamide(3.3 g, 10.0 mmol) in THF (50 mL) diisopropylethylamine (1.9 g, 15.0mmol) was added at 0 IC followed by addition of bromomethyl methyl ether(1.5 9, 12.0 mmol). The reaction mixture was stirred overnight at RT. Towork up the reaction mixture was concentrated and partitioned betweenwater and ethyl acetate. The organic layer was washed with water, brine,dried over MgSO₄, concentrated to give2-carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N-methoxymethyl]thiophenesulfonamideas a greenish oil (3.5 g, 90%).

D.2-Carboxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N-methoxymethyl]thiophenesulfonamide

2-Carbomethoxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N-methoxymethyl]thiophenesulfonamide(3.0 g, 7.8 mmol) in a mixture of THF (30 mL) and 1 N NaOH (30 mL) wasstirred for 3 h at RT. The reaction mixture was diluted with water (20mL) and extracted with ethyl acetate (5 mL). The water solution wasacidified with 1 N HCl then extracted with ethyl acetate. The organicswere washed with water, brine, dried over MgSO₄ and concentrated to give2-carboxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N-methoxymethyl]]thiophenesulfonamideas an oil (quantitative yield).

E.N-(4-chloro-3-methyl-5-isoxazolyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarbonylchloride

To a solution of2-carboxy-3-[N-(4-chloro-3-methylisoxazol-5-yl)-N-methoxymethyl]thiophenesulfonamide(1.5 g, 4.1 mmol) in a mixture of THF (10 mL) and chloroform (5 mL),pyridine (1 drop) was added at 0° C. followed by addition of 2 Msolution of oxalyl chloride (4.5 mL, 9.0 mmol). The reaction mixture wasstirred overnight at RT. To work up the reaction mixture wasconcentrated under reduced pressure to remove all volatiles. The desiredproduct was obtained as a sticky oil which solidifies upon standing.

EXAMPLE 52

N²-(4-Chloro-3-methyl-5-isoxazolyl)-N-(3-hydroxy-2,4,6-trimethylphenyl)-3-sulfamoyl-2-thiophenecarboxamide

A. 3-Acetoxy-2,4,6-trimethylaniline

To a solution of 2,4,6-trimethylphenol (10 g, 73.5 mmol) andtriethylamine (11.1 g, 110.3 mmol) in ethyl acetate (200 mL) was addedacetyl chloride (7.5 g, 95.6 mmol) dropwise at 0° C. The mixture wasstirred overnight. The reaction was quenched with water and the organiclayer was washed with 1 N HCl. The organic layer was dried andconcentrated as usual. The residue was nitrated at RT with 70% HNO₃ andconc. H₂SO₄. The brown reaction mixture was stirred for 1 h, poured intoice-water. The product was extracted into ethyl acetate, the extract waswashed with water, dried over MgSO₄ and concentrated to give the desirednitro compound. This compound was reduced in methanol by sequentialaddition of ammonium chloride and zinc powder. The exothermic reactionwas vigorously stirred until it was back to RT (2 h). To work up thecrude mixture was filtered off and the cake was washed with methanol.The methanolic solutions were concentrated and the residue partitionedbetween ethyl acetate and 1 N NaOH. The organic layer was dried overMgSO₄ and concentrated to give 3-acetoxy-2,4,6-trimethylaniline.

B.N²-(4-Chloro-3-methyl-5-isoxazolyl)-N-(3-hydroxy-2,4,6-trimethylphenyl)-3-sulfamoyl-2-thiophenecarboxamide

N²-(4-Chloro-3-methyl-5-isoxazolyl)-N-(3-hydroxy-2,4,6-trimethylphenyl)-3-sulfamoyl-2-thiophenecarboxamidewas synthesized by reaction of the above amine (Example 52A) with theproduct of Example 51 in THF at 0° C. The reaction mixture was allowedto warm up to RT and stirred for 2 h. To work up the reaction mixturewas poured into 0.05 N HCl and the product was extracted with ethylacetate. The organics were washed with 0.05 N HCl, water, half-saturatedNaHCO₃, water, brine, dried over MgSO₄ and concentrated. Purificationvia column chromatography (silica, 40% ethyl acetate/hexane) gaveN²-(4-chloro-3-methyl-5-isoxazolyl)-N-(3-hydroxy-2,4,6-trimethylphenyl)-N-methoxymethyl-3-sulfamoyl-2-thiophenecarboxamide.A solution of this carboxamide in THF and conc. HCl was stirred at65-72° C. for 3.5 h. To work up the reaction mixture was cooled andpoured into water. The product was taken into ethyl acetate. The extractwas washed with water, brine saturated NaHCO₃, brine, dried over MgSO₄and concentrated as an oil. The acetoxy group was hydrolyzed to thecorresponding hydroxyl during deprotection of the MOM group.N²-(4-chloro-3-methyl-5-isoxazolyl)-N-(3-hydroxy-2,4,6-trimethylphenyl)-3-sulfamoyl-2-thiophenecarboxamidewas obtained as a solid (mp 75-78° C., 54%).

EXAMPLE 53

Assays for Identifying Compounds That Exhibit Endothelin Antagonisticand/or Agonist Activity

Compounds that are potential endothelin antagonists are identified bytesting their ability to compete with ¹²⁵I-labeled ET-1 for binding tohuman ET_(A) receptors or ET_(B) receptors present on isolated cellmembranes. The effectiveness of the test compound as an antagonist oragonist of the biological tissue response of endothelin can also beassessed by measuring the effect on endothelin induced contraction ofisolated rat thoracic aortic rings. The ability of the compounds to actas antagonists or agonists for ET_(B) receptors can be assess by testingthe ability of the compounds are to inhibit endothelin-1 inducedprostacyclin release from cultured bovine aortic endothelial cells.

A. Endothelin Binding Inhibition—Binding Test #1: Inhibition of Bindingto ET_(A) Receptors

TE 671 cells (ATCC Accession No. HTB 139) express ET_(A) receptors.These cells were grown to confluence in T-175 flasks. Cells frommultiple flasks were collected by scraping, pooled and centrifuged for10 min at 190×g. The cells were resuspended in phosphate buffered saline(PBS) containing 10 mM EDTA using a Tenbroeck homogenizer. Thesuspension was centrifuged at 4° C. at 57,800×g for 15 min, the pelletwas resuspended in 5 ml of buffer A (5 mM HEPES buffer, pH 7.4containing aprotinin (100 KIU/ml)) and then frozen and thawed once. 5 mlof Buffer B (5 mM HEPES Buffer, pH 7.4 containing 10 mM MnCl₂ and 0.001%deoxyribonuclease Type 1) was added, the suspension mixed by inversionand then incubated at 37° C. for 30 minutes. The mixture was centrifugedat 57,800×g as described above, the pellet washed twice with buffer Aand then resuspended in buffer C (30 mM HEPES buffer, pH 7.4 containingaprotinin (100 KIU/ml) to give a final protein concentration of 2 mg/mland stored at −70° C. until use.

The membrane suspension was diluted with binding buffer (30 mM HEPESbuffer, pH 7.4 containing 150 mM NaCl, 5mM MgCl₂, 0.5% Bacitracin) to aconcentration of 8 μg/50 μl. ¹²⁵I-endothelin-1 (3,000 cpm, 50 mL) wasadded to 50 μL of either: (A) endothelin-1 (for non specific binding) togive a final concentration 80 nM); (B) binding buffer (for totalbinding); or (C) a test compound (final concentration 1 nM to 100 μM).The membrane suspension (50 μL), containing up to 8 μg of membraneprotein, was added to each of (A), (B), or (C). Mixtures were shaken,and incubated at 4° C. for 16-18 hours, and then centrifuged at 40° C.for 25 min at 2,500×g. Alternatively, the incubation was conducted at24° C. When incubated at 24° C., the IC₅₀ concentrations are 2- to10-fold higher than when the incubation is conducted at 4° C. This, mustbe kept in mind when comparing IC₅₀ concentrations among compoundsprovided herein.

The supernatant, containing unbound radioactivity, was decanted and thepellet counted on a Genesys multiwell gamma counter. The degree ofinhibition of binding (D) was calculated according to the followingequation:${\% \quad D} = {100 - {\frac{(C) - (A)}{(B) - (A)} \times 100}}$

Each test was generally performed in triplicate.

B. Endothelin Binding Inhibition—Binding Test #2: Inhibition of Bindingto ET_(B) Receptors

COS7 cells were transfected with DNA encoding the ET_(B) receptor, Theresulting cells, which express the human ET_(B) receptor, were grown toconfluence in T-150 flasks. Membrane was prepared as described above.The binding assay was performed as described above using the membranepreparation diluted with binding buffer to a concentration of 1 μg/50μl.

Briefly, the COS7 cells, described above, that had been transfected withDNA encoding the ET_(B) receptor and express the human ET_(B) receptoron their surfaces were grown to confluence in T-1 75 flasks. Cells frommultiple flasks were collected by scraping, pooled and centrifuged for10 min at 190×g. The cells were resuspended in phosphate buffered saline(PBS) containing 10 mM EDTA using a Tenbroeck homogenizer. Thesuspension was centrifuged at 4° C. 57,800 X g for 15 min, the pelletwas resuspended in 5 ml of buffer A (5mM HEPES buffer, pH 7.4 containingaprotinin (100 KIU/ml)) and then frozen and thawed once. Five ml ofBuffer B (5 mM HEPES Buffer, pH 7.4 containing 10 mM MnCl₂ and 0.001%deoxyribonuclease Type 1) was added, the suspension mixed by inversionand then incubated at 37° C. for 30 minutes. The mixture was centrifugedat 57,800×g as described above, the pellet washed twice with buffer Aand then resuspended in buffer C (30 mM HEPES buffer, pH 7.4 containingaprotinin (100 KIU/ml) to give a final protein concentration of 2 mg/ml.

The binding assay was performed as described above using the membranepreparation diluted to give 1 μg/50 μl of binding buffer.

C. Test for Activity Against Endothelin-Induced Contraction of IsolatedRat Thoracic Aortic Rings

The effectiveness of the test compound as an antagonist or agonist ofthe biological tissue response of endothelin also is assessed bymeasuring the effect on endothelin induced contraction of isolated ratthoracic aortic rings (see, e.g., Borges et al. (1989) Eur. J.Pharmacol. 165:223-230) or by measuring the ability to contract thetissue when added alone.

Compounds to be tested are prepared as 100 μM stocks. If necessary toeffect dissolution, the compounds are first dissolved in a minimumamount of DMSO and diluted with 150 mM NaCl. Because DMSO can causerelaxation of the aortic ring, control solutions containing varyingconcentrations of DMSO were tested.

The thoracic portion of the adult rat aorta is excised, the endotheliumabraded by gentle rubbing and then cut into 3 mm ring segments. Segmentsare suspended under a 2 g preload in a 10 ml organ bath filled withKrebs'-Henseleit solution saturated with a gas mixture of 95% O₂ and 5%CO₂ (118 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO₄, 1.2 mM KH₂PO₄, 25 mM NaHCO₃,2.5 mM CaCl₂, 10 mM D-glucose).

There is a correlation between activity as an antagonist ofendothelin-induced thoracic aortic ring contraction and activity as aninhibitor of binding of endothelin to endothelin receptors. The pA₂ is alinear function of the log of the IC₅₀.

D. Assay for Identifying Compounds That Have Agonist and/or AntagonisticActivity Against ET_(B) Receptors

1. Stimulation of Prostacyclin Release

Since endothelin-1 stimulates the release of prostacyclin from culturedbovine aortic endothelial cells, the compounds that have agonist orantagonist activity are identified by their ability to inhibitendothelin-1 induced prostacyclin release from such endothelial cells bymeasuring 6-keto PGF_(1α) substantially as described by (Filep et al.(1991) Biochem. Biophys. Res. Commun. 177 171-176. Bovine aortic cellsare obtained from collagenase-treated bovine aorta, seeded into cultureplates, grown in Medium 199 supplemented with heat inactivated 15% fetalcalf serum, and L-glutamine (2 mM), penicillin, streptomycin andfungizone, and subcultured at least four times. The cells are thenseeded in six-well plates in the same medium. Eight hours before theassay, after the cells reach confluence, the medium is replaced. Thecells are then incubated with (a) medium alone, (b) medium containingendothelin-1 (10 nM), (c) test compound alone, and (d) testcompound+endothelin-1 (10 nM).

After a 1 5 min incubation, the medium is removed from each well and theconcentrations of 6-keto PGF_(1α) are measured by a direct immunoassay.Prostacyclin production is calculated as the difference between theamount of 6-keto PGF_(1α) released by the cells challenged with theendothelin-1 minus the amount released by identically treatedunchallenged cells. Compounds that stimulate 6-keto PGF_(1α) releasepossess agonist activity and those which inhibit endothelin-1 6-ketoPGF_(1α) release possess antagonist activity.

2. Inhibition of Sarafotoxin 6c Induced Contraction

Sarafotoxin 6c is a specific ET_(B) antagonist that contracts rat fundalstomach strips. The effectiveness of tests compounds to inhibit thissarafotoxin 6c-induced contraction of rat fundal stomach strips is usedas a measure ET_(B) antagonist activity. Two isolated rat fundal stomachstrips are suspended under a 1 g load in a 10 ml organ bath filled withKrebs'-Henseleit solution containing 10 μMcyclo(D—Asp—Pro—D—Val—Leu—D—Trp) (BQ-1 23; see, U.S. Pat. No. 5,114,918to Ishikawa et al.), 5 μM indomethacin, and saturated with a gas mixtureof 95% 02/5% CO₂. Changes in tension are measured isometrically andrecorded using a Grass Polygraph coupled to a force transducer.Sarafotoxin 6c is added cumulatively to one strip while the second stripis preincubated for 15 min with a test compound prior to addition ofcumulative doses of sarafotoxin 6c. The effects of the test compounds onthe concentration-response curve for sarafotoxin 6c are examined.

E. Deoxycorticosterone Acetate (DOCA)-Salt Hypertensive Rat Model forAssessing in vivo Activity of Selected Compounds

Selected compounds disclosed herein have been tested for activity in thedeoxycorticosterone acetate (DOCA)-salt hypertensive rat model. Toperform these tests, silastic MDX4-4210 elastomer implants containing 47mg (DOCA) were prepared according to the method of Ornmsbee et al.((1973) the J. Pharm. Sci. 62:255-257). Briefly, DOCA is incorporatedinto silicon rubber implants for sustained release. To prepare theimplants the DOCA is incorporated into unpolymerized silicone rubber,catalyst is added and the mixture is cast in a hemicylindrical shape.

Sprague Dawley rats (7-8 weeks old) were unilaterally nephrectomizedunder ketamine anesthesia and a DOCA-implant was placed on the leftlateral dorsal abdomen of the animal. The rats were allowed to recoverfor three weeks. During recovery they were permitted free access tonormal rat chow and 0.9% NaCl drinking solution in place of drinkingwater. The rats develop hypertension within 3 weeks.

All animals were used in the tests between 21 and 30 days post surgery.The mean arterial blood pressure in these animals ranged from 165-200 mmHg.

On the day of experimentation, catheters were inserted under brevitalanesthesia into the right femoral artery for measurement of bloodpressure, and into the right femoral vein for administration of aselected compound. The animals were placed in a restrainer and allowedto recover for a minimum of 60 min or until a steady mean arterial bloodpressure was recorded. At that time, the selected compound or controlvehicle was administered either intravenously, as a 60 minute infusion,or orally by oral gavage. Blood pressure was recorded continuously for afurther 10 hrs.

F. Effect of Intravenous Administration on ET-1-Induced PressorResponses in Conscious, Autonomically Blocked Rats; a Model forAssessing in vivo Activity of Selected Compounds

Male Sprague Dawley rats (250-450 g) were anesthetized (Brevital 50mg/kg, IP) and cannulae were placed in the femoral artery to measuremean arterial pressure (MAP) and in the femoral vein for intravenousdrug administration. Animals were placed in a restrainer and allowed toregain consciousness. Thirty minutes later autonomic blockade wasadministered (atropine methyl nitrate, 3 mg/kg, IV, followed bypropranalol, 2 mg/kg, IV). An hour later animals received a bolusinjection of vehicle (0.5 ml) followed thirty minutes later byintravenous bolus administration of ET-1 (Control, 1 μg/kg). Followingrecovery from this challenge, test-compounds were administered byintravenous bolus administration (0.5 ml) and then re-challenged withET-1 thirty minutes later. Results are expressed as the percentinhibition of the ET-1-induced pressor response after administration ofthe test compound compared to the pressor response induced by thecontrol ET-1 challenge. In some cases a third ET-1 challenge wasadministered ninety minutes after administration of the test compound.

G. Results

1. In vitro

The IC₅₀ for each of the compounds of the preceding Examples for ET_(A)and ET_(B) receptors has been measured. Almost all of the compounds havean IC₅₀ of less than 10 μM for either or both of the ET_(A) and ET_(B)receptors. Many of the compounds have an IC₅₀ less than about 10 μM,others have an IC₅₀ less than about 1 μM and some of the compounds havean IC₅₀ less than about 0.1 μM. A number of the compounds have an IC₅₀for ET_(A) receptors that is substantially less (10 to 100-fold or more)than for ET_(B) receptors, and, thus are selective for ET_(A) receptors.Others of the compounds are ET_(B) selective.

2. In vivo

a. Selected compounds, such asN-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-(4-methyl-phenyl)aminocarbonyl)thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4,-methylenedioxy)benzyl)benzo[b]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[,B-hydroxy(3,4-methylenedioxy)phenylethyl]thiophene-3-sulfonamide,andN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-methylenedioxybenzylcarbonyl)thiophene-3-sulfonamide,have been tested in the hypertensive rat model, and were effective indecreasing blood pressure.

b. Selected compounds, such asN-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)phenyl]acetylthiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)-phenyl]aminocarbonyl}thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methylphenyl)aminocarbonylthiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide,andN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamidehave been tested in the autonomically blocked, normotensive rat modeland shown to have substantial activity, reducing pressure about 30% in30 min at dosages as low as 30 mg/kg, and more than 50% at dosages of 60mg/kg. On the average dosages of 30-60 mg/kg of the test compoundresulted in a 40-60% inhibition of pressor response.

Since modifications will be apparent to those of skill in this art, itis intended that this invention be limited only by the scope of theappended claims.

What is claimed is:
 1. A compound of formula (I):

where Ar¹ is isoxazolyl and Ar² has the formula:

or a pharmaceutically acceptable derivative thereof, wherein: R³ and R⁴are independently selected from the group consisting of hydrogen, halo,cyano, cyanoalkyl, C(O)R⁴¹, alkyl, alkenyl, cycloalkyl and aryl, ortogether form alkylene; W is O, NH or CH₂; R⁵, R⁶ and R⁷ are eachindependently selected as in (i) or (ii), with the proviso that at mostone of R⁵, R⁶ and R⁷ is hydrogen: (i) R⁶ is hydrogen, unsubstitutedalkyl, hydroxy, unsubstituted alkoxy, C(O)R⁴¹, carbamoyloxy oralkoxycarbonyloxy, and R⁵ and R⁷ are each independently selected fromhydrogen, unsubstituted alkyl, hydroxy, C(O)R⁴¹, carbamoyloxy andalkoxycarbonyloxy; or (ii) if at least one of R³ and R⁴ is not hydrogen,then any two may form alkylenedioxy, and the other is selected as in(i); R⁴⁵ is selected from the group consisting of alkyl, C(O)R⁴¹,(CH₂)_(x)OH and CH(OH)(CH₂)_(x)CH₃ in which x is 0-6, S(O)_(n)R⁴¹ inwhich n is 0-2 and C(═NR⁴³)R⁴¹; R⁴¹ is alkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkyl, alkylamino, dialkylamino, arylamino,diarylamino, alkylsulfonylamino, arylsulfonylamino,alkylsulfonylalkylamino, alkylsulfonylarylamino, arylsulfonylalkylaminoor arylsulfonylarylamino; and R⁴³ is selected from hydroxy, alkoxy,alkyl and aryl, wherein R⁴¹ and R⁴³ are unsubstituted or substitutedwith one or more substituents selected from Y, which is alkoxy, halide,pseudohalide, carboxyl, alkoxycarbonyl, aryloxycarbonyl or hydroxy, withthe proviso that the compound is notN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethylphenylaminocarbonyl)-thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamide,N-(3,4-dimethyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)carbonyl]thiophene-3-sulfonamideorN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)-carbonyl]thiophene-3-sulfonamide.2. The compound of claim 1, wherein Ar¹ is 3-isoxazolyl or 5-isoxazolyl.3. The compound of claim 1, wherein: R³ and R⁴ are each independentlyhydrogen, alkyl, halo, cyano, cyanomethyl, acetyl or cycloalkyl, ortogether form alkylene; R⁵, R⁶ and R⁷ are each independently selected asin (i) or (ii), with the proviso that at most one of R⁵, R⁶ and R⁷ ishydrogen: (i) R⁶ is hydrogen, unsubstituted alkyl, hydroxy,unsubstituted alkoxy, C(O)R⁴¹, carbamoyloxy or alkoxycarbonyloxy, and R⁵and R⁷ are each independently selected from hydrogen, unsubstitutedalkyl, hydroxy, C(O)R⁴, carbamoyloxy or alkoxycarbonyloxy; or (ii) if atleast one of R³ and R⁴ is not hydrogen, then any two may formmethylenedioxy, and the other is selected as in (i); x is 0 or 1; n is2; R⁴¹ is alkyl, cycloalkyl, alkylamino, dialkylamino, arylamino,diarylamino, alkylsulfonylamino or arylsulfonylamino; and R⁴³ is hydroxyor alkoxy.
 4. The compound of claim 1, wherein: Ar¹ is4-chloro-3-methyl-5-isoxazolyl; R³ and R⁴ are each independentlyhydrogen, methyl, cyclopropyl, fluoro, chloro, cyano, cyanomethyl oracetyl, or together form propylene; R⁵, R⁶ and R⁷ are each independentlyselected from (i) or (ii), with the proviso that at most one of R⁵, R⁶and R⁷ is hydrogen: (i) R⁶ is selected from hydrogen, methyl, hydroxy,methoxy, acetyl, carbamoyloxy and methoxycarbonyloxy, and R⁵ and R⁷ areeach independently hydrogen, methyl, hydroxy, acetyl, carbamoyloxy andmethoxycarbonyloxy; or (ii) if at least one of R³ and R⁴ is nothydrogen, then R⁶ and R⁷ may form methylenedioxy and R⁵ is selected asin (i); and R⁴⁵ is acetyl, propanoyl, 2-methylpropanoyl,cyclopropylcarbonyl, benzoyl, cyclohexylcarbonyl, methyl,1-hydroxy-1-ethyl, hydroxymethyl, methoxyacetyl, fluoroacetyl,carboxyacetyl, hydroxyacetyl, oximinoacetyl or SO₂R⁴¹.
 5. The compoundof claim 1 selected from the group consisting of:N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide,N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-2,4,6-trimethylphenylcarbamate,3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-2,4,6-trimethylphenylmethyl carbonate,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)-3-thiophenesulfonamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1-methylethyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-ethyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4-methylphenyl)-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6-dimethylphenyl)-2-thiophenecarboxamide,3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thienyl)carbonyl)amino)-3,5-dimethylphenyl)-3-oxopropanoicacid,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6-dimethylphenyl)-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-methylsulfonyl)phenyl)-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((methylamino)sulfonyl)phenyl)-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((dimethylamino)sulfonyl)phenyl)-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-(((methylsulfonyl)amino)carbonyl)phenyl)-2-thiophenecarboxamide3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyl)-4-6-dimethylphenyl)-2-thiophenecarboxamide,N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)aminosulfonyl)-5-methyl-2-thiophenecarboxamide,N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-5-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(5-methylthienyl))carbonyl)amino)-2,4,6-trimethylphenylcarbamate,3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(5-methylthienyl))carbonyl)amino)-2,4,6-trimethylphenylmethyl carbonate,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-5-methyl-3-thiophenesulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)-5-methyl-3-thiophenesulfonamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2(2-hydroxy-1-methylethyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4-methylphenyl)-5-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(5-methylthienyl))carbonyl)amino)-3,5-dimethylphenyl)-3-oxopropanoicacid,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-methylsulfonyl)phenyl)-5-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((methylamino)sulfonyl)phenyl)-5-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((dimethylamino)sulfonyl)phenyl)-5-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-(((methylsulfonyl)amino)carbonyl)phenyl)-5-methyl-2-thiophenecarboxamide.3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyl)-4,6-dimethylphenyl)-5-methyl-2-thiophenecarboxamide,N-(6-acetyl-4-methyl-1,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)aminosulfonyl)-5-methyl-2-thiophenecarboxamide,N-(4-acetyl-6-methyl-1,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide,N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide,N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4-methylthienyl))carbonyl)amino)-2,4,6-trimethylphenylcarbamate,3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4-methylthienyl))carbonyl)amino)-2,4,6-trimethylphenylmethyl carbonate,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-4-methyl-3-thiophenesulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)-4-methyl-3-thiophenesulfonamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1-methylethyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-ethyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2,6-diacetyl)-4-methylphenyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4-methylthienyl))carbonyl)amino)-3,5-dimethylphenyl)-3-oxopropanoicacid,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-methylsulfonyl)phenyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((methylamino)sulfonyl)phenyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((dimethylamino)sulfonyl)phenyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-(((methylsulfonyl)amino)carbonyl)phenyl)-4-methyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyl)-4,6-dimethylphenyl)-4-methyl-2-thiophenecarboxamide,N-(6-acetyl-4-methyl-1,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide,N-(4-acetyl-6-methyl-1,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4-methyl-2-thiophenecarboxamide,N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide,N-(2-benzoyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-hydroxyethanimidoyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-propionylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-isobutyryl-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclohexylcarbonyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(cyclopropylcarbonyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4,5-dimethylthienyl))carbonyl)amino)-2,4,6-trimethylphenylcarbamate,3-(((3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4,5-dimethylthienyl))carbonyl)amino)-2,4,6-trimethylphenylmethyl carbonate,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-methoxy-2,4,6-trimethylphenyl)acetyl)-4,5-dimethyl-3-thiophenesulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-(3-hydroxy-2,4,6-trimethylphenyl)acetyl)-4,5-dimethyl-3-thiophenesulfonamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-1-methylethyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-hydroxy-ethyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2(2,6-diacetyl)-4-methylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-methoxyacetyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(2-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-(4,5-dimethylthienyl))carbonyl)amino)-3,5-dimethylphenyl)-3-oxopropanoicacid,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-glycolyl-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-methylsulfonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((methylamino)sulfonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-((dimethylamino)sulfonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2,4-dimethyl-6-(((methylsulfonyl)amino)carbonyl)phenyl)-4,5-dimethyl-2-thiophenecarboxamide,3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-N-(2-(2-fluoroacetyl)-4,6-dimethylphenyl)-4,5-dimethyl-2-thiophenecarboxamide,N-(6-acetyl-4-methyl-1,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide,N-(4-acetyl-6-methyl-1,3-benzodioxol-5-yl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4,5-dimethyl-2-thiophenecarboxamide,N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-cyclopropyl-2-thiophenecarboxamide,5-acetyl-(N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamide,N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-cyano-2-thiophenecarboxamide,N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-(cyanomethyl)-2-thiophenecarboxamide,N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-fluoro-2-thiophenecarboxamide,N-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-chloro-2-thiophenecarboxamide,andN-2-acetyl-4,6-dimethylphenyl)-5-chloro-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide.6. The compound of claim 5 that is a sodium salt.
 7. The compound ofclaim 6 selected from the group consisting ofN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamideandN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide.8. The compound of claim 1 selected from the group consisting ofN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamideandN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide.9. The compound of claim 1, wherein R³ and R⁴ are hydrogen or methyl.10. The compound of claim 1, wherein R³ and R⁴ are methyl.
 11. Thecompound of claim 1, wherein R³ is methyl and R⁴ is hydrogen.
 12. Thecompound of claim 1, wherein R⁴ is methyl and R³ is hydrogen.
 13. Apharmaceutical composition, comprising the compound of claim 1 in apharmaceutically acceptable vehicle.
 14. The composition of claim 13that is formulated for oral administration.
 15. The composition of claim13 that is formulated for parenteral administration.
 16. The compositionof claim 13 that is formulated as a tablet or capsule.
 17. A process forpreparing a lyophilized powder, comprising: mixing a salt of thecompound of claim 1 with a sufficient amount of a solution containing asugar to produce a solution thereof; sterile-filtering the resultingsolution; and lyophilizing the filtered solution to produce a powder.18. The process of claim 17, wherein the sugar is dextrose or sorbitol.19. A lyophilized powder produced by the method of claim
 17. 20. Thepowder of claim 19, wherein: the pharmaceutically-acceptable salt is acalcium, lithium, magnesium, potassium, sodium hydrogen phosphate,disodium phosphate, sodium or zinc salt.
 21. The powder of claim 19,wherein the pharmaceutically-acceptable salt is a sodium salt.
 22. Acombination, comprising the powder of claim 19 and a sterile vesselcontaining a single dosage or multiple dosage amount thereof.
 23. Thecombination of claim 22, wherein the vessel is an ampoule, vial orsyringe.
 24. A pharmaceutical composition formulated for single dosageor multiple dosage administration prepared by mixing a single dosage ofthe powder of claim 19 with an aqueous medium.
 25. The pharmaceuticalcomposition of claim 24, wherein the final concentration of thesulfonamide salt is between about 1 mg/mL and about 500 mg/mL.
 26. Acombination comprising: a sterile vial containing the pharmaceuticalcomposition of claim
 24. 27. The combination of claim 26, wherein theamount is for single dose administration.
 28. The combination of claim27, wherein the sterile vial also contains an amount of sterile waterfor injection wherein the final concentration of the sulfonamide sodiumsalt is 12.5 mg/mL or 25 mg/mL.
 29. The composition of claim 16,comprising: about 50-100% by weight of the compound; about 0-25% byweight of an diluent or a binder; about 0-10% by weight of adisintegrant; and about 0-5% of a lubricant.
 30. The composition ofclaim 29, wherein: the binder is microcrystalline cellulose; the diluentis lactose; the disintegrant is microscarmellose sodium or sodium starchglycolate; and the lubricant is magnesium stearate.
 31. A method for thetreatment of endothelin-mediated diseases, comprising administering aneffective amount of the composition of claim 13, wherein the effectiveamount is sufficient to ameliorate one or more of the symptoms of thedisease.
 32. The method of claim 31, wherein the compound is a sodiumsalt ofN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamideorN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide.33. The method of claim 31, wherein the disease is selected from thegroup consisting of hypertension, cardiovascular disease, asthma,pulmonary hypertension, inflammatory diseases, ophthalmologic disease,menstrual disorders, obstetric conditions, wounds, gastroentericdisease, renal failure, immunosuppressant-mediated renalvasoconstriction, erythropoietin-mediated vasoconstriction, endotoxinshock, pulmonary hypertension, anaphylactic shock and hemorrhagic shock.34. An article of manufacture, comprising packaging material and a saltof the compound of claim 1 within the packaging material, wherein thecompound is effective for antagonizing the effects of endothelin,ameliorating the symptoms of an endothelin-mediated disorder, orinhibiting the binding of an endothelin peptide to an ET receptor withan IC₅₀ of less than about 10 μM, and the packaging material includes alabel that indicates that the compound salt is used for antagonizing theeffects of endothelin, inhibiting the binding of endothelin to anendothelin receptor or treating an endothelin-mediated disorder.
 35. Thearticle of manufacture of claim 34, wherein the salt is a sodium salt.36. The article of manufacture of claim 34, wherein the compound isselected from the group consisting ofN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamideandN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamideor salts thereof.
 37. The powder of claim 19, wherein the compound is asodium salt ofN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamideorN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide.38. The composition of claim 29, wherein the compound is a sodium saltofN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-2-thiophenecarboxamideorN-(2-acetyl-4,6-dimethylphenyl)-3-(((4-chloro-3-methyl-5-isoxazolyl)amino)sulfonyl)-5-methyl-2-thiophenecarboxamide.39. An alkali metal salt of4-chloro-3-methyl-5-(2-(2-(6-methylbenzo[d][1,3]dioxol-5-yl)acetyl)-3-thienylsulfonamido)isoxazoleprepared by a process comprising the steps of: (a) dissolving the freesulfonamide in an organic solvent; (b) washing the dissolved freesulfonamide with a saturated solution of a salt of the alkali metal; and(c) recovering the alkali metal salt of the sulfonamide.
 40. The alkalimetal salt of claim 39 that is the sodium salt.
 41. A method for thetreatment of endothelin-mediated diseases, comprising administering aneffective amount of the compound of claim 1, wherein the effectiveamount is sufficient to ameliorate one or more of the symptoms of thedisease.
 42. The compound of claim 1, wherein Ar¹ has the formula:

in which R¹ and R² are either (i), (ii) or (iii) as follows: (i) R¹ andR² are each independently selected from H, NH₂, NO₂, halide,pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsulfinyl,alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl,haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl,arylcarbonyl, formyl, substituted or unsubstituted amido, substituted orunsubstituted ureido, in which the alkyl, alkenyl and alkynyl portionscontain from 1 up to about 14 carbon atoms and are either straight orbranched chains or cyclic, and the aryl portions contain from about 4 toabout 16 carbons, except that R² is not halide or pseudohalide; or, (ii)R¹ and R² together form —(CH₂)_(n), where n is 3 to 6; or, (iii) R¹ andR² together form 1,3-butadienyl.
 43. The compound of claim 42, whereinR¹ is halide or methyl; and R² is methyl.
 44. The compound of claim 42,wherein R¹ and R² are each methyl.